Alcantara 2018 Biocatalyzed Synthesis of Antidiabe

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Author(s): Cristina M. Alc

antara, and Andres R. Alcantara
Article title: Biocatalyzed synthesis of antidiabetic drugs: A review
Article no: IBAB_A_1323887
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1 Cristina M. Alcantara
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BIOCATALYSIS AND BIOTRANSFORMATION, 2017
1 https://doi.org/10.1080/10242422.2017.1323887 54
2 55
3 RESEARCH ARTICLE 56
4 57
5 Biocatalyzed synthesis of antidiabetic drugs: A review 58
6 59
7 Cristina M. Alcantaraa and Andres R. Alcantarab 60
8 a
Complutense University of Madrid, Madrid, Spain; bBiotransformations Group, Organic & Pharmaceutical Chemistry Department,
61
9 Q1 Faculty of Pharmacy, Complutense University of Madrid, Madrid, Spain 62
10 63
11 64
ABSTRACT ARTICLE HISTORY
12 The biocatalyzed production of building blocks for synthesizing drugs is a very attractive Received 25 January 2017 65
13 research field, because of the sustainability introduced in a synthetic schedule when chemical Revised 10 March 2017 66
steps are substituted by biocatalyzed protocols. In this article, we will show how different anti- Accepted 29 March 2017
14 67
diabetic drugs, for treating diabetes mellitus Type 1 and Type 2, can be more efficiently and
15 68
effectively synthetized with the help of different types of biocatalysts. The huge overall drug KEYWORDS
16 market for these drugs, as well as the great number of people suffering from diabetes (the 69
Biocatalysis; diabetes; green
17 prevalence of all types of diabetes is growing), makes this topic attractive enough to focus on chemistry; insulin 70
18 more efficient synthetic protocols for preparing antidiabetic drugs. Examples covering biocata- analogues; drugs 71
lyzed synthesis of insulin analogues, sensitizers (PPAR agonists), secretagogues (GLP-1 analogues,
19 GPR119 agonists) and enzyme inhibitors (a-glucosidase inhibitors, DPP4-inhibitors, SGLT-2 inhibi- 72
20 tors and 11b-HSD1 inhibitors) will be presented. 73
21 74
22 75
23 76
24 Introduction Clearly, the prevalence of all types of diabetes is grow- 77
25 ing, particularly Type 2 DM; this can be seen from 78
26 Diabetes mellitus (DM) is a disorder of metabolic 79
2014 data (422 million (World Health Organization
27 homeostasis, showing hyperglycaemia and altered lipid 80
2016; Zhou et al. 2016)) or 2015 (415 million, 1 out of
28 metabolism caused by dysfunction of pancreatic islets, 81
11 adults (International Diabetes Federation 2015)),
29 which do not produce enough insulin (a hormone that 82
while the number of people affected by DM is esti-
30 regulates blood sugar or glucose), or rather caused 83
mated to increase up to 439 million people in 2030,
31 when the body cannot effectively use the insulin it 84
reaching 592 million people by 2035 (World Health
32 produces (World Health Organization 2016). According 85
Organization 2016) and 642 in 2040, which means 1
33 to this, there are three main types of DM (American 86
out of 10 adults (International Diabetes Federation
34 Diabetes Association 2014; Ramachandran et al. 2017); 2015; Ali et al. 2017). 87
35 thus, Type 1 DM results from the inherent pancreas’s Obviously, DM is a major cause of morbidity and 88
36 failure to produce enough insulin, being this type for- mortality in many countries, although 80% of people 89
37 merly known as “insulin-dependent diabetes mellitus” with diabetes live in low- and middle-income countries 90
38 (IDDM) or “juvenile diabetes”. Conversely, Type 2 DM is (International Diabetes Federation 2015; World Health 91
39 caused by insulin resistance, and it was previously Organization 2016); globally, it caused around 5.0 mil- 92
40 referred to as “non-insulin-dependent diabetes lion deaths in 2013 (IDF Diabetes Atlas Group 2015) 93
41 mellitus” (NIDDM) or “adult-onset diabetes”. Finally, 94
and a similar number in 2015 (International Diabetes
42 gestational diabetes is the third main form and occurs 95
Federation 2015). Considering global costs of DM, it
43 when pregnant women without a previous history of 96
has been reported that at least $612 billion were spent
44 diabetes develop high blood sugar levels. 97
globally on diabetes in 2014, representing 11% of all
45 DM is one of the most common chronic conditions 98
global health expenditures. This represents an increase
46 in nearly all countries. In 2014, the International 99
of 12% compared to the data published in 2013 ($548
47 Diabetes Federation (IDF) assessed that 8.2% of adults 100
billion), due to increases in the total number of people
48 101
between 20 and 79 (around 387 million people) were with diabetes (Fernandes et al. 2016). In 2015, 12%
49 102
living with diabetes, an increase compared to 382 mil- of global health expenditure (around $673 billion)
50 103
lion people in 2013 (Fernandes et al. 2016). was dedicated to diabetes treatment and related
51 104
52 CONTACT Andres R. Alcantara andalcan@ucm.es Biotransformations Group, Organic & Pharmaceutical Chemistry Department, Faculty of Pharmacy, 105
53 Q2 Complutense University of Madrid, Campus de Moncloa, E-28040 Madrid, Spain 106
ß 2017 Informa UK Limited, trading as Taylor & Francis Group
2 C. M. ALCANTARA AND A. R. ALCANTARA
107 complications, and the majority of countries spent To focus this article, we will comment some exam- 160
108 between 5% and 20% of their total health expenditure ples illustrating the use of chemoenzymatic protocols 161
109 on DM (International Diabetes Federation 2015; for the sustainable synthesis of antidiabetic drugs. For 162
110 Williams 2016). this purpose, first we will mention some cases in 163
111 Therefore, the world market for diabetes drugs is which biocatalysis has been useful for the preparation 164
112 really huge, $35.6 billion in 2012 (Visiongain 2013), of insulin analogues (treatment of DM Type 1 and 2), 165
113 growing up to 51.1 billion in 2015 (Global Market and subsequently we will focus in the chemoenzy- 166
114 Insight, Inc. 2016), and it is estimated to reach $55.3 matic synthesis of drugs specially designed for the 167
115 billion in 2017 (Visiongain 2013) and more than treatment of Type 2 DM. 168
116 double, $116.1 billion, by 2023 (Global Market Insight, 169
117 Inc. 2016). While Type 1 DM can only be treated with 170
insulin or synthetic insulin analogues (Freeland and
Insulin and insulin analogues
118 171
119 Farber 2016; Zaykov et al. 2016), for the treatment of Semisynthetic human insulin was commercially devel- 172
120 Type 2 DM either insulin or other types of mostly oral oped in the 1970s by Novo Nordisk A/S, starting from 173
121 drugs, either as a single API or a combination of them, porcine insulin, by substituting the B-30 alanine resi- 174
122 can be used (Freeland and Farber 2015; Kokil et al. due of porcine insulin with a threonine residue 175
123 2015; Gaitonde et al. 2016) (Markussen 1981; Andresen and Balschmidt 1982), as 176
124 Taking into consideration all of these data, it is cer- shown in Figure 1. 177
125 tainly understandable that the development of effi- For these biotransformations, five steps were 178
126 cient and sustainable methodologies for synthesizing required (Barfoed 1987): insulin was first extracted 179
127 antidiabetic drugs is highly desirable. For this purpose, from frozen porcine pancreas glands. In a second step, 180
128 the use of biocatalyzed protocols is increasingly of the purified porcine insulin was converted into 181
129 becoming recognized as a very important part inside human insulin in a medium that contains only a small 182
130 Green Chemistry (Malhotra et al. 2015; Sheldon 2016), amount of water and trypsin and a large quantity of 183
131 because those synthetic routes mediated by enzymes organic solvent and threonine ester. Subsequently, 184
132 or cells are generally conducted under mild reaction trypsin hydrolyzed insulin at LysB29-AlaB30, while at the 185
133 conditions, at ambient temperature and can use water same time catalyzed the reverse reaction in which the 186
134 as reaction medium in many cases (Hoyos et al. 2013); threonine ester displaced alanine from position B30 in 187
135 moreover, their high selectivity avoids the need of the insulin molecule. This transpeptidation of porcine 188
136 functional group activation and protection/deprotec- insulin to human insulin was optimized to 97% yield 189
137 tion steps usually required in traditional organic using soluble trypsin (Morihara et al. 1979). This was 190
138 synthesis. Thus, biocatalysis provides processes which followed by chromatographic purification to reduce 191
139 are shorter, produce less waste (generally measured measurable levels of proinsulin and remove the other 192
140 using E-factor value, ratio between the kilograms of reagents, pharmaceutical formulation and distribution 193
141 waste to the kilograms of desired product (Sheldon into the market. Finally, the product was formulated 194
142 2017)) and reduce manufacturing costs and environ- and then filled under sterile conditions, packaged, and 195
143 mental impact. These features are even more signifi- distributed. Transpeptidation was also catalyzed by 196
144 cant in drug synthesis, because it is well known that immobilized trypsin, although the yield was lower 197
145 Pharma Industry produces a great amount of waste, so (80%) (Ueno and Morihara 1989). Another protease, 198
146 that implementing biocatalyzed protocols is increas- from Achromobacter lyticus, was also found to be com- 199
147 ingly being employed (Hoyos et al. 2014; Patel 2016a, pletely specific in the hydrolysis of LysB29-AlaB30 and 200
148 2016b, 2016c). the subsequent condensation con H-Thr-OBut 201
149 202
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152 205
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158 211
159 Figure 1. Semisynthesis of human insulin from porcine insulin by trypsin-catalyzed transpeptidation. 212
BIOCATALYSIS AND BIOTRANSFORMATION 3
213 (Morihara et al. 1980; Morihara and Ueno 1991). Also, caboxypeptidase to delete two Arg residues from 266
214 the use of carboxypeptidase A for the same procedure BThr30, yield the human insulin (Thim et al. 1986; 267
215 was described (Andresen et al. 1983). Ladisch and Kohlmann 1992). 268
216 Human insulin was the first animal protein to be Since those innovative methods, many other proto- 269
217 made in bacteria in a sequence identical to that of the cols based on genetic engineering have been devel- 270
218 human pancreatic peptide, as early as 1978 by oped, and nowadays recombinant human insulin is 271
219 Genentech (lab scale) and Eli Lilly and Co. (scale-up) mainly produced either in E. coli or S. cerevisiae, 272
220 (Johnson 1983), working together to achieve the although several other alternate yeast strains have 273
221 expression of recombinant human insulin in been explored for insulin production, as well as mam- 274
222 Escherichia coli K-12 using genes for the insulin A and malian cells, transgenic animals or plant expression 275
223 B chains; thus, each insulin chain was produced as a systems have been also employed as a host for large- 276
224 b-galactosidase fusion protein in separate fermenta- scale production of recombinant insulin (Walsh 2005; 277
225 tions using E. coli cells transformed with plasmids con- Baeshen et al. 2014). 278
226 taining either the A or B insulin peptide sequence. The On the other hand, by using recombinant DNA 279
227 intracellular products, once removed from the inclu- technology different insulin analogues have been syn- 280
228 sion bodies, were chemically cleavage by CNBr at the thesized. This term refers to an altered form of insulin, 281
229 Met residue between the b-gal and the A or B chains, different from any occurring in nature, still available to 282
230 purified, suffered an oxidative sulfitolysis and chem- the human body for performing the same action as 283
231 ically linked to afford crude insulin. A final purification human insulin in terms of glycaemic control, but dis- 284
232 process led to the first production of recombinant 285
playing improved ADME (absorption, distribution,
233 human insulin, approved by drug regulatory agencies 286
metabolism, and excretion) characteristics (Zaykov
234 in 1982 (Ladisch and Kohlmann 1992). 287
et al. 2016). Officially, the U.S. Food and Drug
235 After this pioneering work, some other strategies 288
Administration (FDA) refers to these as “insulin recep-
236 were developed using recombinant microorganisms 289
tor ligands”, although they are more commonly named
237 that produce intact proinsulin instead of the A or B 290
as insulin analogues, which can be classified into two
238 chains separately. For instance, Novo used 291
239 main classes: 292
Saccharomyces cerevisiae to secrete insulin as a single-
240 chain insulin precursor, in which amino acid 30 of the 293
241 a. those that are more readily absorbed from the 294
B chain of insulin was connected to amino acid 1 of
242 injection site and therefore act faster than natural 295
the A chain by a peptide (Chain C), as shown in
243 insulin injected subcutaneously, intended to sup- 296
Figure 2. Two enzymatic cleavages, the first one cata-
244 lyzed by trypsin leading to the removal of most of ply the bolus level of insulin needed at mealtime 297
245 the C chain, and the second one catalyzed by (prandial insulin) 298
246 299
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261 314
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265 Figure 2. Preparation of human insulin from a precursor. 318
319 b. those that are released slowly over a period of (Howey et al. 1994; Torlone et al. 1994), therefore 372
320 between 8 and 24 h, intended to supply the basal allowing larger amounts of active monomeric insulin 373
321 level of insulin during the day and particularly at to be available for postprandial (after meal) injections 374
322 night time (basal insulin). (Anderson et al. 1997). The second entry in this class, 375
323 insulin aspart (Novolog, Novo Nordisk), was first mar- 376
324 Among fast-action analogues, Eli Lilly and Co. devel- keted in 2000 and utilizes an Asp at position B28 377
325 oped and marketed in 1996 Humalog, the first rapid- (Brange et al. 1988; Home et al. 1998, 2000). The most 378
326 acting insulin analogue (insulin lispro rDNA). This recent rapid-acting analogue, insulin glulisine (Apidra, 379
327 analogue was engineered through recombinant DNA Sanofi), was marketed in 2006 and is based on 380
328 technology, so that the penultimate lysine and proline replacements of LysB29 with Glu and of AsnB3 with Lys 381
329 residues on the C-terminal end of the B-chain (Becker et al. 2005; Dreyer et al. 2005; Becker and Frick 382
330 (ProB28LysB29) were reversed (Figure 3). This modifica- 2008). 383
331 tion did not alter the insulin receptor binding, but Considering those analogues intended to control 384
332 blocked the formation of insulin dimers and hexamers basal insulin levels, insulin glargine (Lantus, Sanofi), 385
333 386
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371 Figure 3. Some insulin analogues. 424
425 launched in 2001, uses a shift in isoelectric point insulin (Freeland and Farber 2016; Pettus et al. 2016; 478
426 (achieved through two additional Arg residues at posi- Zaykov et al. 2016; Sherr et al. 2017) and new and 479
427 tions B31 and B32) in order to dramatically lower solu- faster formulations (Sherr et al. 2017), because there is 480
428 bility at physiological pH, rendering the insulin far less little to no alternatives to brand-named analogue insu- 481
429 soluble at the injection site. This results in an lin and non-analogue human alternatives for treating 482
430 extended time–action profile as the analogue slowly both types of DM in low- and middle-income countries 483
431 re-solubilizes (Rosenstock et al. 2001). Additionally, a (Kaplan and Beall 2017). 484
432 Gly residue is introduced at position A21 to maintain 485
433 chemical stability in the aqueous, acidic formulation. 486
Other antidiabetic drugs
434 Another different tactic consists in attaching a long- 487
435 chain fatty acid with the purpose of slowing adsorp- Inside this category we will include: 488
436 tion and facilitating extended plasma circulation 489
437 through non-covalent albumin binding. This strategy a. drugs that increase the sensitivity of target organs 490
438 was reported by Eli Lilly with insulin lipidated at to insulin, called sensitizers 491
439 LysB29 with palmitic acid (W99-S-32) (Myers et al. b. agents that increase the amount of insulin 492
440 1995) and by Novo Nordisk with LysB29-myristyl secreted by the pancreas, known as 493
441 desB30-insulin, launched in 2006 under the name of secretagogues 494
442 insulin detemir (Levemir) (Havelund et al. 2004; c. agents that decrease the rate at which glucose is 495
443 Hermansen et al. 2006). Very recently, two new basal absorbed from the gastrointestinal tract. 496
444 insulin analogues completed Phase III trials (Pettus d. enzyme inhibitors 497
445 et al. 2016): insulin degludec (Tresiba, Novo Nordisk), a 498
446 des-B30 human insulin that is uniquely fatty-acylated We will show now different examples of biocata- 499
447 at LysB29 with hexadecanedioic acid via gamma-L-glu- lyzed synthesis of some of these compounds. The use 500
448 tamyl spacer (Wang et al. 2012; Gough et al. 2013), of biocatalysts is especially adequate for the stereo- 501
449 which have been recently approved by FDA in the selective synthesis of those drugs possessing at least 502
450 USA, and insulin peglispro (Ly2605541), derived by one stereogenic centre. 503
451 covalent attachment of a linear 20 kD polyethylene 504
452 505
glycol (PEG) polymer to the LysB28 side-chain in insu- Sensitizers
453 lin lispro (Henry et al. 2014). 506
454 Drugs belonging to this category are biguanides (such 507
Generally speaking, the use of synthetic biology for
455 as metformin, 1), thiazolidinediones (TZDs, also named 508
creating cell factories is the methodology used at
456 glitazones, 2), and glitazares 3), shown in Figure 4. The 509
industrial scale in the preparation of these insulin ana-
457 first class is represented by metformin, the first-line 510
logues (Baeshen, Baeshen et al. 2014; Sanchez-Garcia
458 medication for the treatment of Type 2 DM (Maruthur 511
et al. 2016). For sure, the improvement of metabolic
459 et al. 2016; Wise 2016), which is synthetized only by 512
pathways for increasing their production can be classi-
460 classical chemical methods, so that we will mention 513
fied as sequential (or cascade) biocatalytical processes,
461 the other two classes, glitazones and glitazars. 514
and not many examples of protease modifications of
462 precursors leading to insulin analogues, which can be 515
463 Peroxisome proliferator-activated receptors (PPAR) 516
sensu stricto considered biotransformations, can be
464 agonists 517
found in literature (Bogsnes et al. 2003; Habermann
465 518
and Zocher 2008). Anyway, ample research is being The PPARs are ligand-dependent transcription factors.
466 519
carried out in the development of new analogues of The three mammalian PPARs (a, b/d and c)
467 520
468 521
469 522
470 523
471 524
472 525
473 526
474 527
475 528
476 529
477 Figure 4. General structure of insulin sensitizers. 530
531 (Nevin et al. 2011; Wright et al. 2014) are crucial regu- Jamali et al. 2008), as also shown in Figure 5. 584
532 lators of fatty acid and lipoprotein metabolism, glu- Consequently, in animal models, the individual enan- 585
533 cose homeostasis, cellular proliferation/differentiation tiomers and racemates of glitazones appear to show 586
534 and the immune response. Therefore, PPARs are key equivalent activity as antidiabetic agents, so that most 587
535 targets in the treatment of metabolic disorders such as synthetic methodologies are conducted following con- 588
536 insulin resistance and Type 2 DM; furthermore, PPARs ventional chemical steps (Ortiz and Sansinenea 2011). 589
537 are also involved in chronic inflammatory diseases However, Parks et al. (1998), through the in vitro 590
538 such as atherosclerosis, arthritis, chronic pulmonary analysis of rosiglitazone enantiomers in a PPARc- 591
539 inflammation, pancreatitis, inflammatory bowel dis- binding assay, suggested that the (S)-isomer is the 592
540 ease, psoriasis, blood pressure regulation, neuroinflam- main responsible for the antidiabetic activity, and a 593
541 mation, nerve-cell protection, inflammatory pain similar behaviour of the (S)-eutomer was described for 594
542 reduction, and hypothalamic control of metabolism rivoglitazone, another glitazone which failed to reach 595
543 (Menendez-Gutierrez et al. 2012). However, PPAR-c, the drug market (Izumi et al. 2013). On the other 596
544 which is expressed in adipose tissue, lower intestine, hand, pioglitazone is currently undergoing clinical tri- 597
545 and cells involved in immunity, is the most extensively als for treatment of Alzheimer’s disease (AD): when 598
546 investigated PPAR, while PPAR-d, which regulates mice were dosed with racaemic pioglitazone, the con- 599
547 several metabolic processes, has also been investi- centration of (R)-(þ)-pioglitazone was 46.6% higher 600
548 gated for the development of new drugs for treating than that of (S)-()-pioglitazone in brain tissue and 601
549 DM (Wright et al. 2014). 67.7% lower than that of (S)-pioglitazone in plasma, 602
550 There are three marketed TZDs, acting as PPAR-c and dosing mice with pure (R)-pioglitazone led to a 603
551 agonist: pioglitazone (2a, ActosTM or GlustinTM, Takeda 76% increase in brain exposure levels compared to 604
552 Pharmas USA and Eli Lilly), rosiglitazone (2b, those from an equivalent dose of racaemic 605
553 AvandiaTM, GlaxoSmithKline), and lobeglitazone (2c, pioglitazone (Chang et al. 2015). Furthermore, pure 606
554 DuvieTM, Chong Kun Dang), whose chemical structures (R)-pioglitazone was also shown to have comparable 607
555 are shown in Figure 5. Common for the chemical amyloid-lowering capabilities to the racaemic pioglita- 608
556 structure of TZDs compounds is the chiral centre at zone in an in vitro AD model, so that dosing with (R)- 609
557 610
the C-5 of the ring, prone to racemization at physio- pioglitazone instead of the racaemic mixture may
558 611
logical pH (Welch et al. 2003; Rippley et al. 2007; result in higher levels of brain exposure to
559 612
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575 628
576 629
577 630
578 631
579 632
580 633
581 634
582 635
583 Figure 5. Chemical structure of glitazones. 636
637 pioglitazone, thus potentially improving the develop- possess a common chemical structure (2-methyl-2-ary- 690
638 ment of pioglitazone treatment of AD. loxypropionic acids or esters), not displaying any chiral 691
639 Thus, it is possible to find in literature some exam- centre. In an attempt to obtain an enantiopure PPAR-a 692
640 ples of the resolution of both enantiomer of agonist, Astra Zeneca synthesized AZD 4619 (Figure 7, 693
641 glitazones, either through their derivatization to dia- (S)-6), an a agonist, by means of an enzymatic 694
642 stereoisomers (Sohda et al. 1984; Gahafu et al. 2010; dynamic kinetic resolution (DKR) of the corresponding 695
643 van Niel et al. 2011a, 2011b) or by preparative chiral racaemic thioester, using an organic base to promote 696
644 HPLC (Calixto and Bonato 2013). On the other hand, the racemization (Brown et al. 2006), as shown 697
645 the first example of stereoselective biocatalytic synthe- in Figure 7. 698
646 sis was described by researchers at SmithKline The thioester rac-5 was resolved with Pseudomonas 699
647 Beecham by means of the bioreduction of the precur- cepacia lipase in the presence of a tert-amine base, tri- 700
648 sor benzylidine compound 4 (Figure 6), catalyzed by octylamine. The desired acid (S)-6 is stable, and 701
649 whole cells from red yeast Rhodotorula rubra CBS 6469 residual (R)-thioester was racemized by deprotonation 702
650 (Cantello et al. 1994). and reprotonation catalyzed by the organic base, 703
651 These authors observed that the bioreduction pro- which cannot make a similar undesired racemization 704
652 ceeded at basic pH values with a high degree of step of (S)-6, because the a protons of the carboxylate 705
653 stereoselectivity, but that the product was undergoing product are not acidic enough to be deprotonated by 706
654 racemization, the rate of racemization being slower tert-amine bases. Although this process was scaled to 707
655 than the rate of product formation under these condi- grams, AZD 4619 was discontinued because of hepato- 708
656 tions. Thus, the biotransformation was carried out toxicity problems detected in Phase I (Thulin et al. 709
657 under acidic pH conditions. Over a 4 h reaction at pH 2008). Similarly, the resolution of the racaemic alpha- 710
658 3.75, the product was found to be of >98% enantio- chloro thioester intermediate 7 has been described 711
659 meric purity. These authors also described the use of using the same strategy, shown in Figure 8 (Dow et al. 712
660 713
alginate-entrapped immobilized cells for performing 2012). Remarkably, the use of a protease instead of a
661 714
the bioreduction (Cantello et al. 1994), which was fur- lipase allowed the synthesis of the antipode (R)-8,
662 715
ther scaled-up by some other scientists of the same although with a lower ee (90% with Savinase versus
663 716
company (Heath et al. 1997). 98% with lipase).
664 717
On the other hand, PPAR-a agonists serve as cellu- Glitazars (Figure 9) are dual PPAR a/c agonists
665 718
lar receptor for fibrates, a class of drugs used in the that improve the lipid profile and exert an antidia-
666 719
treatment of dyslipidaemia, and also used for the betic action, similar to a combination of a fibrate
667 720
treatment of vascular complications associated with and a thiazolidinedione, so that they are
668 721
Type 2 DM (Verges 2004; Steiner 2007). These fibrates considered as “two drugs in one” (Wilding 2012).
669 722
670 723
671 724
672 725
673 726
674 727
675 728
676 729
677 730
Figure 6. Biocatalyzed synthesis of (R)-(þ)-rosiglitazone.
678 731
679 732
680 733
681 734
682 735
683 736
684 737
685 738
686 739
687 740
688 741
689 Figure 7. DKR process to synthesize AZD 4619. 742
743 796
744 797
745 798
746 799
747 800
748 801
749 802
750 803
751 804
752 805
753 806
754 807
755 808
756 809
Figure 8. DKR process to synthesize a precursor of AZD 4619.
757 810
758 811
759 812
760 813
761 814
762 815
763 816
764 817
765 818
766 819
767 820
768 821
769 822
770 823
771 824
772 825
773 826
774 827
775 828
776 829
777 830
778 831
779 832
780 833
781 834
782 835
783 836
784 837
785 838
786 839
787 840
788 841
789 842
790 843
791 844
792 845
793 846
794 847
795 Figure 9. Some glitazars. 848
849 902
850 903
851 904
852 905
853 906
854 907
855 908
856 909
857 910
858 911
859 912
860 Figure 10. Chemical synthesis of (S)-2-ethoxy-3-(4-hydroxyphenyl)propanoic acid ((S)-9) starting form L-tyrosine.
913
861 914
862 915
863 916
864 917
865 918
866 919
867 920
868 921
869 922
870 923
871 924
872 925
873 926
874 927
875 928
876 929
877 930
878 931
879 Figure 11. Enzymatic kinetic resolution of rac-17 by an enantioselective hydrolysis. 932
880 933
881 934
882 Ragaglitazar (Figures 9 and 10) was discontinued by accepted for launch in India by the Drug Controller 935
883 Novo Nordisk and Dr. Reddy’s Laboratories because General of India (DCGI) for the treatment of diabetic 936
884 of its adverse effects after detecting urinary bladder dyslipidaemia or hypertriglyceridaemia in patients 937
885 938
tumour in mice. After different clinical trials, in May with Type II DM not controlled by statins alone
886 939
2006 the two glitazars most advanced in develop- (Agrawal 2014; Sharma et al. 2015; Dwivedi et al.
887 940
ment at that time, muraglitazar (16, PargluvaTM, 2015b).
888 941
developed by Brystol Myers Squibb) and tesaglitazar As can be seen, the structure of (S)-2-ethoxy-3-(4-
889 942
(11, GalidaTM, Astra Zeneca) were discontinued. In hydroxyphenyl)propanoic acid ((S)-9, shown in bold
890 943
fact, 16 was associated with an increased incidence font in Figure 9) is common feature for many glitazars;
891 944
of heart failure, while ragaglitazar 10 was associated its synthesis has been described starting from L-tyro-
892 945
with decreased glomerular filtration (Conlon 2006). sine (Dwivedi et al. 2014), in a rather dull 4-step meth-
893 946
894 Some other newer glitazars are aleglitazar 13, from odology depicted in Figure 10. 947
895 Hoffmann-La Roche (Wilding 2012), which has been Therefore, establishing an alternative greener meth- 948
896 discontinued in July 2013 after Phase III trials, and odology using biocatalyzed protocols would be highly 949
897 cevoglitazar 15 (Chen et al. 2010; LBM-642, from desirable. In fact, in the synthesis of ragaglitazar 950
898 Novartis AG), which failed to pass Phase I. Very (Figure 11), the key intermediate (S)-9 was obtained 951
899 recently, in June 2013, the Indian company Zydus through a very mild enantioselective hydrolysis of the 952
900 Cadila has presented LipaglynTM (Saroglitazar 14), racaemic ethyl ester 17, catalyzed by an esterase from 953
901 the first glitazar to be approved in the world, Aspergillus oryzae; this process was run on a 44 kg pilot 954
955 1008
956 1009
957 1010
958 1011
959 1012
960 1013
961 1014
962 1015
963 1016
964 1017
965 1018
966 1019
967 1020
968 1021
969 1022
970 1023
971 1024
972 1025
973 1026
974 1027
975 1028
976 Figure 12. Enzymatic kinetic resolution of rac-18a and 18b by an enantioselective hydrolysis. 1029
977 1030
978 1031
979 1032
980 1033
981 1034
982 1035
983 1036
984 1037
985 1038
986 1039
987 1040
988 1041
989 1042
990 1043
991 1044
992 1045
993 1046
994 1047
995 1048
996 1049
997 1050
998 Figure 13. Preparation of enantiopure ethyl-(S)-2-ethoxy-3-(p-methoxyphenyl)propanoate (EEHP) (S)-19a by bioreduction. 1051
999 1052
1000 scale, to produce enantiopure ragaglitazar (S)-10 in 43- a-chymotrypsin-catalyzed hydrolysis of racaemic 18a 1053
1001 48% yields with ee values between 98.8% and 99.6% or 18b, and subsequent work up to finally obtain 1054
1002 (Deussen et al. 2003). (S)-20a or (S)-20b with moderate overall yields 1055
1003 On the other hand, Brenna and coworkers have (Brenna et al. 2009a) (Figure 12). 1056
1004 reported two different biocatalytic approaches Due to the lower yield obtained, this research 1057
1005 to obtain another enantiopure precursor for the group decided to change to a reductase-catalyzed 1058
1006 preparation of glitazars. In a first strategy, the prep- strategy, depicted in Figure 13(a), finally leading to the 1059
1007 aration of (S)-20a or (S)-20b was initiated by an corresponding compounds (S)-19 (after chemical 1060
1061 1114
1062 1115
1063 1116
1064 1117
1065 1118
1066 1119
1067 1120
1068 1121
1069 1122
1070 1123
1071 1124
1072 1125
1073 1126
1074 1127
1075 1128
1076 1129
1077 1130
1078 1131
1079 1132
1080 1133
1081 1134
1082 1135
1083 1136
1084 1137
Figure 14. Preparation of enantiopure methyl (S)-2-bromobutyrate (S)-26 and (S)-2-bromobutyric acid (S)-24 by bioreduction.
1085 1138
1086 1139
oxidation of (S)-22) in good yield of 78% and an excel- ester 25. By using baker’s yeast, it was possible to pre-
1087 1140
lent ee of 99%, using baker’s yeast and an in situ sub- pare the corresponding (S)-2-bromobutyric acid (S)-24
1088 1141
strate feeding product removal (SFPR) technique (78% conversion, 97% ee) starting from the same sub-
1089 1142
(Brenna et al. 2009b). Nevertheless, it suffers from (i) strate. These enantiopure molecules can be useful as
1090 1143
an extremely low productivity (0.39 g L1 d1), (ii) a chiral building blocks in the preparation of compounds
1091 1144
nonquantitative conversion, (iii) a complex purification such as 27 (Liu et al. 2009) or 28 (Acton et al. 2009),
1092 1145
process based on the chemoselective oxidation of the 3-acyl-1-(phenyl or benzyl)indolecarboxylic acids which
1093 1146
byproduct, the undesired allylic alcohol, and (iv) a use- were also tested as PPAR-c modulators (Pirat et al.
1094 1147
less and counterproductive reduction of the carbonyl 2012).
1095 1148
group (by alcohol dehydrogenases present in baker’s
1096 1149
yeast) since the final target is an ester. Therefore,
1097 Secretagogues 1150
1098 Brenna and coworkers improved the methodology 1151
(Figure 13(b)) by using a genetically engineered ene- These are drugs that increase insulin output from the
1099 1152
reductase (Old Yellow enzyme, OYE) from S. cerevisiae pancreas, and they can be divided in two main types:
1100 1153
expressed in E. coli, and glucose dehydrogenase for sulfonylureas and non-sulfonylureas secretagogues. As
1101 1154
1102 cofactor regeneration; thus, it was possible to improve long as most of sulfonylureas do not possess any 1155
1103 the productivity (up to 55.6 g L1 d1, 74% yield, 98% chiral centre in their structures, their syntheses are car- 1156
1104 ee), at gram scale (Bechtold et al. 2012) in the prepar- ried out following classical chemical methodologies. 1157
1105 ation of the desired ethyl-(S)-2-ethoxy-3-(p-methoxy- There are different types of non-sulfonylureas secre- 1158
1106 phenyl)propanoate (EEHP) (S)-19a, ultimately obtained tagogues. For instance, meglitinides, which bind to an 1159
1107 through chemical oxidation of intermediate aldehyde ATP-dependent Kþ (KATP) channel on the cell mem- 1160
1108 (S)-23. brane of pancreatic beta cells in a similar manner to 1161
1109 Using this same cloned OYE, a similar strategy sulfonylureas (Proks et al. 2002), although with weaker 1162
1110 (Figure 14) has been developed by the same group binding affinity and faster dissociation (Dornhorst 1163
1111 (Brenna et al. 2012) for the preparation of enantiopure 2001). The only described example in which a biocata- 1164
1112 methyl 2-bromobutyrate (S)-26 (100% conversion, 97% lyzed protocol is employed in the synthesis of this 1165
1113 ee) starting from the corresponding Z-a,b-insaturated type of compounds is the preparation of (S)-(þ)-3- 1166
1167 1220
1168 1221
1169 1222
1170 1223
1171 1224
1172 1225
1173 1226
1174 1227
Figure 15. Preparation of enantiopure (S)-(þ)-3-methyl-1-(2-(1-piperidinyl)phenyl)butylamine (S)-29.
1175 1228
1176 1229
1177 methyl-1-(2-(1-piperidinyl)phenyl)butylamine (S)-29 meglitinides, due to their lower risk of causing hypo- 1230
1178 through enzymatic catalysis, as described in Figure 15 glycaemia (Garber 2012). 1231
1179 (Zhao et al. 2010). Like so, (S)-2-amino-3-(6-o-tolylpyridin-3-yl)propa- 1232
1180 This reaction was carried out in AcOEt, acting as noic acid (S)-32, Figure 16, is a key intermediate 1233
1181 solvent and acyl donor, and the enzyme used was needed for synthesis of GLP-1 mimics or GLP-1 recep- 1234
1182 Novozyme 435, a commercial preparation of immobi- tor modulators: its synthesis has been described using 1235
1183 lized lipase from Candida antarctica. The yields were three different enzymatic procedures (Chen et al. 1236
1184 not very high, although the use of an immobilized bio- 2011); in the first one, depicted in Figure 16, (S)-32 1237
1185 catalyst allows its recycling to afford pure (S)-29 and was prepared (gram scale) in 68% solution yield and 1238
1186 the subsequent synthesis of repaglinide 31 (PrandinTM, 54% isolated yield (100% ee), starting from racaemic 1239
1187 Novo Nordisk) (Scott 2012). 32 using a recombinant (R)-amino acid oxidase from 1240
1188 Trigonopsis variabilis, cloned and overexpressed in E. 1241
1189 GLP-1 analogues coli and then immobilized on Celite, and an (S)-amino 1242
1190 acid dehydrogenase from Sporosarcina ureae. The 1243
The main role of pancreatic b cells, to synthesize and
1191 cofactor NADH required for the reductive amination 1244
secrete insulin, is somewhat modulated by a group of
1192 reaction was regenerated using formate and formate 1245
heterotrimeric G proteins, which are the immediate
1193 dehydrogenase (FDH). 1246
downstream targets of diverse G protein-coupled
1194 In a second strategy (Figure 17), (S)-32 could be 1247
receptors (GPCRs). Hence, different GPCRs expressed
1195 prepared in 73% isolated yield with 99.9% ee from 1248
by pancreatic b cells regulate insulin secretion, and
1196 racaemic amino acid using the same initial enzyme, 1249
therefore these compounds, acting as insulin secreta-
1197 (R)-amino acid oxidase from T. variabilis expressed in 1250
gogues, are potential therapeutic targets for treating
1198 E. coli, but now in combination with an (S)-amino- 1251
Type 2 DM (Ahren 2009; Lovshin and Drucker 2009).
1199 transferase (purified from a soil organism identified 1252
One of them is the receptor for the glucagon-like
1200 1253
peptide-1 (GLP-1R), which binds to and is activated by as Burkholderia sp., also cloned and expressed in E.
1201 1254
glucagon-like peptide-1 (GLP-1), a 30 amino acid resi- coli), and using (S)-aspartate as amino donor. This
1202 1255
due peptide, originated from preproglucagon, synthe- procedure had the advantage that both enzymes
1203 1256
sized in the L-cells in the distal ileum, in the pancreas could be added at the start of reaction in a one-pot
1204 1257
and in the brain. GLP-1 is member of the incretin hor- system, and several batches containing 9.11 g (15 g
1205 1258
mone family, a term that refers to the observation that of the monosulfate monohydrate) of rac-32 were run
1206 1259
orally administered glucose results in a larger increase in a 2-L reactor at 30 C 22 h, to produce 85% yield
1207 1260
in plasma insulin levels and insulin-dependent (73% after crystallization, ee 99.9%). Hence, the reac-
1208 1261
decrease in blood glucose concentration when com- tion was scaled up with 607 g (1 kg of the monosul-
1209 1262
1210 pared to the same amount of glucose given intraven- fate monohydrate) of rac-32 to give a 66% isolated 1263
1211 ously (Rondas et al. 2013). Then, injectable GLP-1 yield of (S)-32 as the monosulfate monohydrate 1264
1212 mimetics (synthetic polypeptides such as exenatide (ee 99.9%). 1265
1213 (Amylin Pharmaceuticals, ByettaTM/BydureonTM), lira- Finally, a cyclic deracemization of rac-32 by 1266
1214 glutide (Novo Nordisk, VictozaTM, SaxendaTM), lixisena- (R)-selective oxidation was developed using Celite- 1267
1215 tide (Sanofi, LyxumiaTM), albiglutide (GSK, TanzeumTM), immobilized (R)-amino acid oxidase, in combination 1268
1216 dulaglutide (Eli Lilly, TrulicityTM), taspoglutide (phase III with chemical imine reduction using the borane- 1269
1217 halted Sept 2010) or semaglutide are used in the treat- ammonia complex (Figure 18). Before the imine 34 1270
1218 ment Type 2 DM, displaying an advantage over older (bounded to the enzyme as initial product of the oxi- 1271
1219 insulin secretagogues, such as sulfonylureas or dase reaction) gets hydrolyzed to the keto acid 31, the 1272
1273 1326
1274 1327
1275 1328
1276 1329
1277 1330
1278 1331
1279 1332
1280 1333
1281 1334
1282 1335
1283 1336
1284 1337
1285 1338
1286 1339
1287 1340
1288 1341
1289 1342
1290 1343
1291 1344
1292 1345
1293 1346
1294 1347
1295 Figure 16. Synthesis of (S)-32 using a (R)-amino acid oxidase and an (S)-amino acid dehydrogenase. 1348
1296 1349
1297 1350
1298 1351
1299 1352
1300 1353
1301 1354
1302 1355
1303 1356
1304 1357
1305 1358
1306 1359
1307 1360
1308 1361
1309 1362
1310 1363
1311 1364
1312 1365
1313 1366
1314 1367
1315 1368
1316 1369
1317 1370
1318 Figure 17. Synthesis of (S)-32 using a (R)-amino acid oxidase and an (S)-aminotransferase. 1371
1319 1372
1320 borane-ammonia reduces it to regenerate rac-32 in a GPR119 agonists 1373
1321 dynamic process. Through this strategy, a maximum 1374
1322 The GPCR 119 (GPR119, also named “glucose-depend- 1375
yield of 76–79%, was obtained at pH 6.0–7.0, with ee
1323 ent insulinotropic receptor”) is a recent potential tar- 1376
values reaching >99.9% at pH 6–8 using 10 equiv. of
1324 get for the development of oral antidiabetic drugs 1377
the borane–ammonia complex. (Overton et al. 2008; Ritter et al. 2016). In fact, more
1325 1378
1379 than 20 pharmaceutical companies have been devel- pyrimidinylpiperidinyloxypyridone analogues 39 1432
1380 oping GPR119 agonists, but many clinical candidates (Figure 19) possessing chirality (Broekema et al. 2013), 1433
1381 have been discontinued for different reasons not and for this purpose, an scalable synthesis of enan- 1434
1382 always explained (Buzard et al. 2012; Ritter et al. 2016). tiomers of N-substituted 3-hydroxypyrrolidin-2-ones 1435
1383 For instance, Bristol-Myers Squibb, after disclosing have been recently reported (Singh et al. 2015), as 1436
1384 some pyridone, pyridazone, benzothiazole, dihydro- shown in Figure 19. 1437
1385 benzofuran, bicyclic pyrimidines and piperidinyl Thus, lipase PS 30 from P. cepacia immobilized on 1438
1386 sulfone GPR119 agonists (Wacker et al. 2014; Ye et al. polypropylene catalyzed the enantioselective esterifica- 1439
1387 2014), is working now on some new tion of racaemic-1-(2-fluoro-4-iodophenyl)-3-hydroxy- 1440
1388 pyrrolidin-2-one 35 with succinic anhydride and 1441
1389 2-methyltetrahydrofuran at 4 C, leading to (S)-35 in 1442
1390 high enantiomeric excess >99% and yield 40%, after 1443
1391 an easy separation from (R)-36 (Singh et al. 2015). 1444
1392 Following the initial experiments, it was possible to 1445
1393 scale-up to 50 g/L of substrate; in this process, after 1446
1394 8.5 h, immobilized enzyme was removed by simple fil- 1447
1395 tration, and (S)-35 was isolated in 40% yield and 1448
1396 ee >99%. 2-Methyltetrahydrofuran, a green biosolvent 1449
1397 (Pace et al. 2012, 2014) served as a reaction medium 1450
1398 and a solvent to extract the desired compound from 1451
1399 the reaction mixture, eliminating the use of chroma- 1452
1400 Figure 18. Synthesis of (S)-32 using an (R)-amino acid oxidase tography. On the other hand, Novozyme 435 (C. ant- 1453
combined with a chemical racemization protocol. arctica lipase B) was employed for the resolution of
1401 1454
1402 1455
1403 1456
1404 1457
1405 1458
1406 1459
1407 1460
1408 1461
1409 1462
1410 1463
1411 1464
1412 1465
1413 1466
1414 1467
1415 1468
1416 1469
1417 1470
1418 1471
1419 1472
1420 1473
1421 1474
1422 1475
1423 1476
1424 1477
1425 1478
1426 1479
1427 1480
1428 1481
1429 1482
1430 1483
1431 Figure 19. Enzymatic resolution of N-substituted 3-hydroxypyrrolidin-2-ones. 1484
1485 racaemic acetate 37 for obtaining the desired alcohol Figure 20, 40), precursor of the commercialized 1538
1486 (R)-38 in 37% isolated yield and high enantiomeric Miglitol 41 (GlysetTM, Pfizer) or Miglustat 42 1539
1487 excess (ee >99.4%). This process was scaled up to kg (ZavescaTM, Actelion). Other type of iminocyclitols 1540
1488 scale (two successive campaigns (4.1 kg, ee >99.4% described in that review by Alcantara and coworkers 1541
1489 and 5.5 kg, ee >99.5%), and the major disadvantage of are polyhydroxylated pyrrolidines, such as 2,5-dideoxy- 1542
1490 a kinetic resolution (using only 50% of starting mater- 2,5-imino-D-mannitol 43, commonly known as DMDP, 1543
1491 ial) was overcome by recycling the undesired enantio- found in many plants and microorganisms, have been 1544
1492 mer into the desired enantiomer via Mitsunobu studied for their antihyperglycaemic properties (Horne 1545
1493 inversion (probed at gram scale) (Singh et al. 2015). et al. 2011). A representative member of polyhydroxy- 1546
1494 lates indolizidine 44 is the toxic alkaloid castanosper- 1547
1495 mine, a potent inhibitor of lysosomal a-glucosidase 1548
Enzyme inhibitors
1496 (Lahiri et al. 2013). DNJ, DMDP, and castanospermine 1549
1497 The inhibition of enzymes involved in metabolic path- also inhibit glycoprotein-processing enzymes to vary- 1550
1498 ways is undoubtedly one of the most active areas ing degrees (Asano et al. 2000). Casuarine 45 is an 1551
1499 inside Medicinal Chemistry (Harriman et al. 2010; example of a pyrrolizidines, which are also isolated 1552
1500 Copeland 2013). There are many enzymatic processes from plants and have been used in the treatment of 1553
1501 which inhibition could lead to a beneficial effect on breast cancer, diabetes, and bacterial infections 1554
1502 patients suffering from diabetes; in fact, two main (Wardrop and Waidyarachchi 2010). Finally, Calystegine 1555
1503 types of enzyme inhibitors, such as a-glucosidase A3 46 belongs to nortropane-type alkaloids possessing 1556
1504 inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors glycosidase inhibitory activity (Asano et al. 2000). 1557
1505 have already been commercialized and frequently pre- The chemoenzymatic preparation of another type 1558
1506 scribed, while some others are still under evaluation at of a-glucosidase inhibitors, aminocyclitols, are also 1559
1507 different (pre)clinical stages. In the following sections, described in the above-mentioned review (Alcantara 1560
1508 we will describe both types, showing how biocatalysis et al. 2014), illustrating biocatalyzed protocols for syn- 1561
1509 can help in the synthesis of their chemical structures. thesizing Voglibose 47 (VoglibTM, marketed by Mascot 1562
1510 Health Series), or Acarbose 48, generic sold in Europe 1563
1511 a-Glucosidase inhibitors and China as GlucobayTM (Bayer AG), in North America 1564
1512 as PrecoseTM (Bayer Pharmaceuticals), and in Canada 1565
It is well known that inhibitors of intestinal
1513 as PrandaseTM (Bayer AG). 1566
a-glucosidase enzymes promote a delay in the absorp-
1514 1567
tion of sugars because of the retard in the final steps
1515 DPP-4 inhibitors 1568
of carbohydrate digestion, so that they are useful for
1516 1569
reducing postprandial hyperglycaemia in DM (Derosa DPP-4, also known as adenosine deaminase complex-
1517 1570
and Maffioli 2012; Campo et al. 2013). These a-glucosi- ing protein 2 or CD26 (cluster of differentiation 26) is
1518 1571
dase inhibitors act as glycomimetics, because they a homodimer protein consisting of 766 amino acids
1519 1572
1520 bear a certain grade of resemblance to the natural car- with cytoplasmic, transmembrane, and extracellular 1573
1521 bohydrates, but the differential part of their structure regions, playing a pivotal role in glucose metabolism, 1574
1522 promotes a blockade of enzymatic action (Ernst and because it is responsible for the degradation of the 1575
1523 Magnani 2009). The use of iminosugars (N atom GLP-1 incretins previously mentioned. In fact, DPP-4 is 1576
1524 replacing O) (Winchester 2009; Horne et al. 2011), thio- a serine exodipeptidase highly specific in recognizing 1577
1525 sugars (S instead of O) (Witczak and Culhane 2005) or peptide substrates with proline or alanine in the last 1578
1526 carbasugars (ethereal bridge substituted by a methy- position (P1) prior to the scissile amide bond of the 1579
1527 lene) (Mayato et al. 2012) as glycomimetics is a well- N-terminal of incretins (Deacon and Holst 2013). 1580
1528 developed strategy. More specifically, iminosugars Thus, DPP4 inhibitors are a pharmacological class 1581
1529 mimics transition state (oxocarbenium) of glycosidases of glucose-lowering agents that open up new per- 1582
1530 mechanism, due to the nitrogen protonation at spectives for Type 2 DM treatment because of their 1583
1531 physiological pH values (Caines et al. 2007; Winchester unique mechanism of action (Scheen 2012; Deacon 1584
1532 2009). Recently, Alcantara and coworkers published a and Holst 2013; Mize and Salehi 2013). Furthermore, 1585
1533 review covering chemo-enzymatic protocols for syn- recently the cardioprotective effects of these com- 1586
1534 thesizing this type of glycomimetics (Alcantara et al. pounds have been described (Dai et al. 2013; Wang 1587
1535 2014). These authors described the biocatalyzed syn- et al. 2013; Juillerat-Jeanneret 2014), so that this 1588
1536 thesis of different iminocyclitols, such as the polyhy- type of drugs, called generically gliptins and shown 1589
1537 droxylated piperidine 1-deoxynojirimycin (DNJ, in Figure 21, are becoming increasingly more studied 1590
1591 1644
1592 1645
1593 1646
1594 1647
1595 1648
1596 1649
1597 1650
1598 1651
1599 1652
1600 1653
1601 1654
1602 1655
1603 1656
1604 1657
1605 1658
1606 1659
1607 1660
1608 1661
1609 1662
1610 1663
1611 1664
1612 1665
1613 1666
1614 1667
1615 1668
Figure 20. Some inhibitors of a-glucosidases.
1616 1669
1617 (Mittermayer et al. 2015; Cahn et al. 2016; Doggrell Sitagliptin is the most widely sold DPP-4 inhibitors in 1670
1618 and Dimmitt 2016; Thomas et al. 2016), as they are the USA and worldwide, reaching sales of US$6358 1671
1619 commonly used as second-line therapy for diabetes million in 2014 with an expected rise to 7525 in 2020. 1672
1620 1673
in high-income regions (Cahn et al. 2016). Sitagliptin was the second leading antidiabetic product
1621 1674
Although in many cases, purely chemical syntheses in 2014, after insulin glargine, and is predicted to be
1622 1675
have been described for the preparation of gliptins, the leading product by 2020 (Cahn et al. 2016;
1623 1676
there are some very attractive examples of biocata- Fernandes et al. 2016).
1624 1677
lyzed protocols for preparing the homochiral building The first chemical synthesis of sitagliptin (Hansen
1625 1678
blocks required for their synthesis; in some cases, the et al. 2009) involved in asymmetric hydrogenation of
1626 1679
chirality comes directly from commercially available an enamine 65 using a rhodium-based chiral catalyst
1627 1680
proline, which is transformed either into (S)-pyrrolidine (Rh[Josiphos]) at high pressure (Figure 22); neverthe-
1628 1681
2-carbonitrile, as for the preparation of anagliptin 56 less, this process is not stereoselective enough (97%
1629 1682
(Kato et al. 2011), or into the corresponding proline ee), and the final product is contaminated with rho-
1630 1683
amide, as required for the synthesis of Vildagliptin 50 dium, so that different additional purification steps are
1631 1684
(Pellegatti and Sedelmeier 2015). In other cases, chiral- required. Some other chemical syntheses have been
1632 1685
1633 ity comes from other compounds, and these examples recently reviewed by Davies et al. (2015). 1686
1634 will be commented in the following paragraphs. Nevertheless, an enzymatic process has substantially 1687
1635 improved the efficiency of sitagliptin manufacturing 1688
1636 Sitagliptin. Sitagliptin (Figure 21, 49) (sold under the (Savile et al. 2010a, 2010b); in fact, using an engi- 1689
1637 trade name JanuviaTM by Merck Sharp & Dhome) was neered transaminase, developed at Codexis by rational 1690
1638 the first marketed oral antihyperglycaemic drug design, a biocatalyst with broad applicability towards 1691
1639 belonging to the gliptin family (Aroda et al. 2012). the synthesis of chiral amines was obtained. Under 1692
1640 Sitagliptin can be used either alone or combined with optimal conditions, the best variant converted 200 g/L 1693
1641 metformin or thiazolidinedione, another oral antihy- prositagliptin ketone 64 (Figure 22) to sitagliptin 49 1694
1642 perglycaemic agents in the treatment of Type 2 DM, with a 92% yield and an enantiomeric excess higher 1695
1643 already commented before (Kim et al. 2005). that 99%, by using 6 g/L enzyme in 50% dimethyl 1696
1697 1750
1698 1751
1699 1752
1700 1753
1701 1754
1702 1755
1703 1756
1704 1757
1705 1758
1706 1759
1707 1760
1708 1761
1709 1762
1710 1763
1711 1764
1712 1765
1713 1766
1714 1767
1715 1768
1716 1769
1717 1770
1718 1771
1719 1772
1720 1773
1721 1774
1722 1775
1723 1776
1724 1777
1725 1778
1726 1779
1727 1780
1728 1781
1729 1782
1730 1783
1731 1784
1732 1785
1733 1786
1734 1787
1735 1788
1736 1789
1737 1790
1738 1791
1739 1792
1740 1793
1741 Figure 21. Chemical structure of several DPP4 inhibitors registered for clinical uses (49–60) and some other discontinued ones 1794
1742 (61–63). 1795
1743 1796
1744 1797
1745 sulfoxide. The biocatalytic process provides sitagliptin total manufacturing cost. Furthermore, the enzymatic 1798
1746 with a 10–13% increase in overall yield compared to reaction is run in multipurpose vessels, so that special- 1799
1747 the chemical process, a 53% increase in productivity ized high pressure hydrogenation equipment is no 1800
1748 (kg/L per day), a 19% reduction in total waste, the longer needed. Full details of this process, which 1801
1749 elimination of all heavy metals, and a reduction in obtained the Presidential Green Chemistry Challenge 1802
1803 1856
1804 1857
1805 1858
1806 1859
1807 1860
1808 1861
1809 1862
1810 1863
1811 1864
1812 1865
1813 1866
1814 1867
1815 1868
1816 1869
1817 1870
1818 1871
1819 1872
1820 1873
1821 1874
1822 1875
1823 1876
1824 1877
1825 1878
1826 1879
1827 1880
1828 1881
1829 1882
1830 1883
1831 1884
1832 1885
1833 1886
1834 1887
Figure 22. Chemical versus biocatalyzed synthesis of JanuviaTM, sitagliptin phosphate 66.
1835 1888
1836 Award (Greener Reaction Conditions Award) from the as depicted in Figure 23. A modified form of a recom- 1889
1837 1890
U.S. Environmental Protection Agency (EPA) in 2010 binant phenylalanine dehydrogenase cloned from
1838 1891
(http://www.epa.gov/greenchemistry/pubs/pgcc/past. Thermoactinomyces intermedius and expressed in Pichia
1839 1892
html), can be found in literature (Moore et al. 2012; pastoris as well as in E. coli was used for this process
1840 1893
Willies et al. 2012; Busto et al. 2016). Since this innova- development and scale-up. NADþ produced during
1841 1894
tive approach of biocatalyzed synthesis of sitagliptin the reaction was recycled to NADH using FDH cloned
1842 1895
using transaminases, other similar examples have been and overexpressed in E. coli. The modified phenylalan-
1843 1896
described (Hou et al. 2016; Wei et al. 2016). ine dehydrogenase contains two amino acid changes
1844 1897
at the C-terminus and a 12 amino acid extension of
1845 1898
Saxagliptin. Saxagliptin (OnglyzaTM, 51) is another the C-terminus (Hanson et al. 2007). The production of
1846 1899
inhibitor of DPP-4 developed by Bristol-Myers Squibb multikilogram batches was originally carried out with
1847 1900
1848 (Kania et al. 2011). This compound inhibits DDP-4 by extracts of P. pastoris expressing the modified phenyl- 1901
1849 covalent bonding to the catalytic serine presented in alanine dehydrogenase from T. intermedius and 1902
1850 DDP-4 active site (Aroda et al. 2012). Its synthesis endogenous FDH. The reductive amination process 1903
1851 (Savage et al. 2009) requires (S)-N-Boc-3-hydroxyada- was further scaled up using a preparation of the two 1904
1852 mantylglycine 69 as a key chiral intermediate. For its enzymes, FDH and phenylalanine dehydrogenase, 1905
1853 preparation, a process for conversion of the keto acid expressed in a single recombinant E. coli. The amino 1906
1854 67 to the corresponding amino acid 68 using acid 68 was directly protected as its Boc derivative 69 1907
1855 (S)-amino acid dehydrogenases was developed, without isolation to afford the intermediate. 1908
1909 1962
1910 1963
1911 1964
1912 1965
1913 1966
1914 1967
1915 1968
1916 1969
1917 1970
1918 1971
1919 1972
1920 1973
1921 1974
1922 1975
1923 1976
1924 1977
1925 1978
1926 1979
1927 1980
1928 1981
Figure 23. Enzymatic preparation of two intermediates in the synthesis of saxagliptin 51.
1929 1982
1930 1983
Yields before isolation were close to 98% with 100% improvement (79% amide and 13% side-products), as
1931 1984
ee. This process has now been used to prepare several well as the use of sodalime and ascarite, respectively,
1932 1985
hundred kilograms of 69 to support the development at 200 g/L in the reaction headspace (increase in
1933 1986
and manufacturing of saxagliptin. amide yield to 84 and 95%), this presumably by way
1934 1987
Also (S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1- of adsorption of carbon dioxide liberated from the
1935 1988
carboxylic acid,1-(1,1-dimethylethyl)-ester 70 is decomposition of ammonium carbamate. A further
1936 1989
required in the synthetic scheme for obtaining saxa- increase in yield to 98% was attained via the com-
1937 1990
gliptin. Direct chemical ammonolysis was hindered by bined use of 100 g/L of calcium chloride and 200 g/L
1938 1991
reaction conditions, which resulted in unacceptable of ascarite. A prep-scale reaction with the process
1939 1992
levels of amide racemization and side-product forma- ester feed was used. So, in the optimized process, 70
1940 1993
1941 tion, whereas milder two-step hydrolysis condensation (220 g/L) was reacted with 90 g/L (1.25 mol equiv.) of 1994
1942 protocols using coupling agents such as 4-(4,6-dime- ammonium carbamate, 33 g/L (15% w/w of ester 1995
1943 thoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride input) of CAL-B, 110 g/L calcium chloride, and 216 g/L 1996
1944 (DMT-MM), were compromised by reduced overall of ascarite (in the headspace) and run at 50 C for 3 1997
1945 yields (Kunishima et al. 2001). To address this issue, a days. Complete conversion of ester was achieved, with 1998
1946 biocatalytic procedure was developed, based upon the the formation of 96% (182 g/L) of 71 and 4% of side- 1999
1947 CAL-B-mediated ammonolysis of 68 with ammonium products; finally, after workup, 98% potency amide in 2000
1948 carbamate to furnish amide 71 without racemization >99.9% ee was isolated in 81% yield (Gill and Patel 2001
1949 and with low levels of side-product formation (Gill and 2006). 2002
1950 Patel 2006). Experiments utilized process stream ester 2003
1951 feed, which consisted of 22% w/v (0.91 M) of the Aloglitin, linagliptin and trelagliptin. As can be seen 2004
1952 ester in toluene. Since the latter precluded the use of in Figure 24, three gliptins, alogliptin 52, linagiptin 53 2005
1953 free ammonia due to its low solubility in toluene, solid and trelagliptin 58 shared a common moiety, (R)-piper- 2006
1954 ammonium carbamate was employed. Reactions were idin-3-amine (R)-74, in their chemical structures, which 2007
1955 performed using a mixture of neat process feed, apropos is the only chiral centre present in these 2008
1956 ammonium carbamate (71 g/L, 2 mol equiv. of ammo- drugs. Therefore, this enantiopure amine is required in 2009
1957 nia), and biocatalyst (25 g/L) and shaken at 400 rpm, the chemical synthesis of 52 (Feng et al. 2007a, 2007b; 2010
1958 50 C. Under these conditions, CAL-B provided optically Ludescher et al. 2010), 53 (Eckhardt et al. 2007) and 2011
1959 pure amide 71 with yields of 69%, together with 21% 58 (Zhang et al. 2011). Although there are different 2012
1960 of side-products (by HPLC). The inclusion of drying chemical methods to produce optically pure (R)-74, 2013
1961 agents such as calcium chloride gave significant the use of transaminases allows very clean 2014
2015 2068
2016 2069
2017 2070
2018 2071
2019 2072
2020 2073
2021 2074
2022 2075
2023 2076
2024 2077
2025 2078
2026 2079
2027 2080
2028 2081
2029 2082
2030 2083
2031 2084
2032 2085
2033 2086
2034 2087
2035 2088
Figure 24. Enzymatic transaminase-catalyzed kinetic resolution of 72 to produce enantiopure (R)-74.
2036 2089
2037 2090
2038 2091
2039 2092
2040 2093
2041 2094
2042 2095
2043 2096
2044 2097
2045 2098
2046 2099
2047 Figure 25. Enzymatic preparation of (R)-74, through a transaminase-catalyzed asymmetric synthesis.
2100
2048 2101
2049 2102
2050 methodologies. Thus, Hoehne et al. (2008) described production of (R)-74 starting from Cbz-protected pyr- 2103
2051 the kinetic resolution of racaemic N-protected 3-ami- imidine-3-one 73, and a subsequent deprotection of 2104
2052 nopiperidine 72, as shown in Figure 24. the correspondent amine (R)-72 allowed a good yield 2105
2053 In this process, the x-transaminase of Alcaligenes (up to 92%) of (R)-74 (Yang et al. 2014). Furthermore, 2106
2054 denitrificans (AdeTA) was the selected catalyst for the similar results regarding yield and optical purity could 2107
2055 kinetic resolution of 72, which was coupled to the sim- be obtained starting from Boc- or Bn-protected pyrimi- 2108
2056 ultaneous transformation of pyruvic acid into L-Ala, dine-3-one. 2109
2057 and the desired amine (R)-72 was obtained with 41% Recently, a similar approach has been proposed 2110
2058 isolated yield and 97% ee. This transaminase was also employing a recombinant transaminase from 2111
2059 tested in the synthesis of homologous N-protected Mycobacterium vanbaalenii, both as isolated enzyme 2112
2060 3-aminopyrrolidine, through an analogous kinetic reso- and whole cells (and also in their immobilized forms), 2113
2061 lution. Anyhow, the drawback of these resolutions is leading to good yield and optical purity (Luo et al. 2114
2062 their inherent limited yield (max. 50%). 2016). 2115
2063 On the other hand, enantiopure (R)-74 can be syn- 2116
2064 thesized using a transaminase-catalyzed asymmetric Teneligliptin and gosogliptin. Teneligliptin 55 is a 2117
2065 synthesis (not limited to 50% yield), as depicted in DPP4-inhibitor initially developed by Mitsubishi 2118
2066 Figure 25. In this process, the use of a transaminase Tanabe Pharma under the name of TeneliaTM (recently 2119
2067 and isopropilamine as sacrificial substrate allowed the available also in Argentina (TenegluconTM) and India 2120
2121 2174
2122 2175
2123 2176
2124 2177
2125 2178
2126 2179
2127 2180
2128 2181
2129 2182
2130 2183
2131 2184
2132 2185
2133 2186
2134 2187
2135 2188
2136 Figure 26. Schematic synthesis of teneligliptin 55 and gosogliptin 60. 2189
2137 2190
2138 2191
(TenepureTM; TenezaTM) at relatively affordable price,
2139 2192
with an unique structure characterized by five con-
2140 2193
secutive rings, explaining its powerful activity and its
2141 2194
extremely long half-life (24.2 h), with resulting DPP-4
2142 2195
inhibition throughout the day (Scott 2015; Pujadas
2143 2196
et al. 2016; Sharma et al. 2016). Gosogliptin 60 was
2144 2197
developed by Pfizer, but it was discontinued in 2012
2145 2198
in Phase II trials; on June 2012 exclusive rights were Figure 27. Synthesis of Hyp 75 catalyzed by P4H.
2146 2199
granted to SatRx LLC, a Russian company, for further
2147 2200
development, and it was launched in Russian market are usually difficult to process (Huttel 2013; Wu et al.
2148 2201
in 2016 under the trade name SatRxTM. 2016).
2149 2202
As can be seen in Figure 26, teneligliptin 55 and Another chemoenzymatic methodology for produc-
2150 2203
gosogliptin 60 share a somehow similar structure, in ing Hyp starts from racaemic ethyl 2-Boc-amino-4-pen-
2151 2204
which the chirality in the molecule is introduced by tenoate 78, obtained from the corresponding
2152 2205
using enantiopure N-Boc-trans-4-hydroxy-L-proline (76, malonate derivative 77, as shown in Figure 28
2153 2206
Figure 26), as described for teneligliptin (Yoshida et al. (Krishnamurthy et al. 2014).
2154 2207
2012; Dwivedi et al. 2015a) and gosogliptin (Lafrance Racaemic 78 is resolved by enantioselective
2155 2208
2156 and Caron 2012). hydrolysis catalyzed by subtilisin, leading to acid 2209
2157 4-(R)-Hydroxyproline (Hyp, 75) is a non-proteino- (S)-79, which is subsequently converted into the ben- 2210
2158 genic amino acid present in collagen, and which cylic ester and epoxidized, to furnish diastereomers 80 2211
2159 abundance among the residues in animal proteins is (69% yield, 57:43 (2S,4R):(2S,4S), as detected by NMR). 2212
2160 very high, around 4%, a value calculated from the Amine deprotection with HCl (4M in dioxane) for 2.5 h 2213
2161 abundance of collagen amongst animal proteins (1/3) quantitatively produced the hydrochloride 81 (not iso- 2214
2162 and that of Hyp within collagen (38% 1/3). There lated) as a white solid upon solvent evaporation. 2215
2163 are different biocatalyzed methodologies for the syn- Subsequently, 81 was dissolved in DMF (4.6 mmol in 2216
2164 thesis of 75; the most obvious one requires the 30 mL DMF), and two equivalents of Et3N were added 2217
2165 employ of prolyl 4-hydroxylase (P4H, E.C. 1.14.11.2, to neutralize HCl. After 72 h, TLC results showed the 2218
2166 also named procollagen-proline 4-dioxygenase), an disappearance of 81, and 1H NMR analysis of the 2219
2167 2-oxoacid dioxygenase requiring 2-oxoglutaric acid evaporated reaction mixture showed the absence of 2220
2168 and molecular oxygen as cosubstrates (Gorres and characteristic methylene epoxide signals, strongly sug- 2221
2169 Raines 2010), as depicted in Figure 27. Nevertheless, gest that the nucleophilic ring opening of the 81 2222
2170 although there are many references for this proced- occurred intramolecularly, possibly to produce both 2223
2171 ure at lab scale (Hara et al. 2014; Yi et al. 2014; Chen cis- and trans-diastereomers of L-hydroxyproline benzyl 2224
2172 et al. 2015; Pozzolini et al. 2015), its technical applica- ester 82. Nonetheless, these products were not iso- 2225
2173 tion is limited, because these 2-oxoacid dioxygenases lated, and this reaction mixture was re-dissolved in 2226
2227 2280
2228 2281
2229 2282
2230 2283
2231 2284
2232 2285
2233 2286
2234 2287
2235 2288
2236 2289
2237 2290
2238 2291
2239 2292
2240 2293
2241 2294
2242 2295
2243 2296
2244 2297
2245 2298
2246 2299
2247 2300
2248 2301
2249 2302
2250 2303
2251 2304
2252 2305
2253 2306
2254 2307
Figure 28. Chemoenzymatic synthesis of Hyp ester 83.
2255 2308
2256 2309
2257 2310
2258 2311
2259 2312
2260 2313
2261 2314
2262 2315
2263 2316
2264 2317
2265 2318
2266 2319
2267 2320
2268 2321
2269 2322
2270 2323
2271 2324
2272 2325
2273 2326
2274 2327
2275 2328
2276 2329
2277 2330
Figure 29. Chemoenzymatic synthesis of (R)-ProP 91.
2278 2331
2279 2332
2333 2386
2334 2387
2335 2388
2336 2389
2337 2390
2338 2391
2339 2392
2340 2393
2341 2394
2342 2395
2343 2396
2344 2397
2345 2398
2346 2399
2347 2400
2348 2401
2349 2402
2350 2403
2351 2404
2352 2405
2353 Figure 30. Enantioselective preparation of both enantiomers of benzyl-2-(dimethoxyphosphoryl)pyrrolidine-1-carboxylate 94. 2406
2354 2407
2355 2408
2356 2409
2357 dioxane and reacted with a small excess of Boc2O 86 mediated by a lipase from Aspergillus niger, as 2410
2358 using Et3N to re-protect the secondary amino groups, depicted in Figure 29 (Wuggenig et al. 2011). 2411
2359 and to furnish after 24 h both diastereomers N-Boc-cis- Subsequently, the a-hydroxyphosphonate (S)-87 2412
2360 L-hydroxyproline benzyl ester (cis-(S,S)-83) and (obtained in 40% yield and 86% ee) was mesylated in 2413
2361 N-Boc-trans-L-hydroxyproline benzyl ester (trans-(S,R)- 93% yield and then selectively converted (NaN3/18- 2414
2362 83), as a yellow oil. Column chromatography (silica crown-6/MeCN/24 h/reflux) into the monoazide (S)-88 2415
2363 gel, hexane–50% EtOAc (v/v) as eluent) allowed the in 91% yield; subsequently, a Staudinger reaction with 2416
2364 separation of L-cis-hydroxyproline lactone (S,S)-84 Ph3P in DMF furnished the intermediate iminophos- 2417
2365 (obtained via intramolecular cyclization, white solid, phorane (S)-89, which cyclized to the protected 2418
2366 29–42%) and the desired Hyp ester cis-(S,S)-83 L-phosphaproline (R)-90, and after deprotection and 2419
2367 (yellowish oil, 18–38%). purification yielded (R)-ProP 91. 2420
2368 Recently, a kinetic resolution of racaemic ProP has 2421
2369 Other DPP4 inhibitors: phosphoproline containing been described (Arizpe et al. 2015), using lipases for 2422
2370 dipeptides. Dipeptides containing phosphoproline the enantioselective synthesis of carbamates, as 2423
2371 (ProP, the phosphonic counterpart of proline) are depicted in Figure 30. 2424
2372 known to inhibit several serine DPP4 proteases, as well The starting racaemic dimethyl pyrrolidin- 2425
2373 as other serine proteases (Boduszek et al. 1994; 2-ylphosphonate 92 was chemically derived from pyr- 2426
2374 Moonen et al. 2004; Mucha et al. 2011). For preparing rolidin-2-one. Different lipases were tested to check 2427
2375 these enantiopure dipeptides, it is thus mandatory to the best option for enantioselective alkoxycarbonyla- 2428
2376 prepare homochiral ProP, which chemical asymmetric tion with several carbonates; best results were 2429
2377 synthesis (Katritzky et al. 1999; Davis et al. 2004; Ma obtained using allyl 3-methoxyphenylcarbonate and 2430
2378 et al. 2011; Ordon~ez et al. 2015) or chemical resolution C. antarctica lipase type A (CAL-A), which catalyzed the 2431
2379 by diastereomers preparation (Kaboudin et al. 2013) allyloxycarbonylation of rac-92 to yield the unreacted 2432
2380 have been described in literature. substrate (S)-92 with 90% ee and the allyl carbamate 2433
2381 The development of biocatalyzed protocols for the (R)-93 with 20% ee (Figure 30) after 92 h of reaction. 2434
2382 preparation of enantiopure ProP is a very recent Nevertheless, separation of these compounds by silica- 2435
2383 research area, and not many cases have been gel column chromatography was not possible, because 2436
2384 described; in fact, (R)-ProP was obtained by kinetic reso- of the lability of 92, so that the crude obtained from 2437
2385 lution of d-bromo-a-(chloroacetoxy)butylphosphonate the enzymatic reaction was treated with benzyl 2438
2439 2492
2440 2493
2441 2494
2442 2495
2443 2496
2444 2497
2445 2498
2446 2499
2447 2500
2448 2501
2449 2502
2450 2503
2451 2504
2452 2505
2453 Figure 31. Enantioselective preparation of carbamates of ProP dimethyl esters. 2506
2454 2507
2455 chloroformate to give a mixture of optically active car- C-glycosidic bond, but now between the aglycon and 2508
2456 bamates (S)-94 and (R)-93, which could be separated, the corresponding 5-thio-D-glucopiranose. 2509
2457 and finally (R)-93 was converted into (R)-94. In all Remogliflozin etabonate 102 is the only member of 2510
2458 cases, the enantiomers could be separated by chiral the family possessing the classical O-linkage, 2511
2459 chromatography (Arizpe et al. 2015). These same while tofogliflozin 100 is a spiranic compound, so that 2512
2460 authors described a somehow simpler protocol by C- and O-linkages are simultaneously presented. 2513
2461 using benzyl 3-methoxyphenyl carbonate for catalyz- Any biocatalytic method for creating the 2514
2462 ing the carbamoylation (after 84 h, 82% of (R)-94 and C-glycoside would demand the use of Leloir C-glycosil- 2515
2463 94% ee of (S)-92), and then an easier separation by a transferases (C-GTs) (Gutmann and Nidetzky 2013), but 2516
2464 previous tosilation of non-converted (S)-92 (Figure 31). this possibility has not been developed for gliflozins, 2517
2465 as far as we know. Nevertheless, empagliflozin 98 2518
2466 Sodium–glucose co-transporter 2 (SGLT2) inhibitors: does contain a chiral fragment in its structure, (S)- 2519
2467 gliflozins tetrahydrofuran-3-ol (S)-103, required for the synthesis 2520
2468 of the drug (Wang et al. 2014), and different biotrans- 2521
2469 Sodium–glucose co-transporters or sodium–glucose- 2522
linked transporter (SGLTs) play an important role in formations can be found in literature for producing
2470 2523
the intake and elimination of glucose. SGLTs are both enantiomers of 103, as shown in Figure 33. The
2471 2524
located in the intestinal mucosa (enterocytes) of the first strategy is based on a kinetic resolution of the
2472 2525
small intestine (SGLT1), and the proximal tubule of the corresponding racaemic alcohol, but this is not that
2473 2526
nephron (SGLT2 in proximal convoluted tubule, SGLT1 trivial because of the small differences in the size of
2474 2527
in proximal straight tubule). SGLT2 is the main respon- both groups attached to the carbinol moiety: in fact,
2475 2528
sible for reabsorption of glucose in kidney; thus, inhib- Baumann and coworkers did not find any measurable
2476 2529
ition of SGLT2 would lead to a very low or even null enantioselectivity in the hydrolysis of different racae-
2477 2530
glucose reabsorption and an increased glycosuria, mic tetrahydrofuran-3-yl esters after testing more than
2478 2531
highly desirable for patients suffering Type 2 DM 100 commercial hydrolases (Baumann et al. 2000).
2479 2532
(Madaan et al. 2016; Solini 2016). Using enzymes modified by mutations of amino acids
2480 2533
2481 There are several SGLT2 inhibitors, called generically it became possible to increase the enantioselectivity in 2534
2482 gliflozins, already marketed (Figure 32): dapagliflozin the hydrolysis, but only up to a moderate value 2535
2483 96, canagliflozin 97, empagliflozin 98, ipragliflozin 99, (enantiomeric ratio E ¼ 10, compared to E ¼ 4.3 with 2536
2484 tofogliflozin 100, and luseogliflozin 101 are approved the wild-type enzyme) using the D31T/L93F double 2537
2485 in different countries, and the prodrug remogliflozin mutant of an esterase from Bacillus stearothermophilus 2538
2486 etabonate 102 is under study for commercialization (Nobili et al. 2013). 2539
2487 (Madaan et al. 2016). Similarly, the bioreduction of the corresponding 2540
2488 The chemical structures of dapagliflozin 96, canagli- ketone dihydrofuran-3(2H)-one 105 did not lead to 2541
2489 flozin 97, empagliflozin 98 and ipragliflozin 99 present high enantioselectivity values, once again because of 2542
2490 a C-glycosidic linkage between the glucose moiety the similar size of both methylene groups around the 2543
2491 and the aglycon; luseogliflozin 101 also possess the carbonyl moiety; in fact, Sun et al. (2016) tested this 2544
2545 2598
2546 2599
2547 2600
2548 2601
2549 2602
2550 2603
2551 2604
2552 2605
2553 2606
2554 2607
2555 2608
2556 2609
2557 2610
2558 2611
2559 2612
2560 2613
2561 2614
2562 2615
2563 2616
2564 2617
2565 2618
2566 2619
2567 2620
2568 2621
2569 2622
2570 2623
2571 2624
2572 2625
2573 2626
2574 2627
2575 2628
2576 2629
2577 2630
2578 2631
2579 2632
2580 2633
2581 2634
2582 2635
Figure 32. Some marketed gliflozins.
2583 2636
2584 2637
2585 2638
2586 bioreduction using two commercial ADH kits An indirect biocatalyzed methodology for produc- 2639
2587 (47 enzymes), describing only a 22% ee for the best ing (S)-103 was described by Pienaar et al. (2008), 2640
2588 (R)-selective enzyme and 91% ee for the best (S)- using a chemoenzymatic approach also presented in 2641
2589 selective one, but under suboptimal conversions. So, Figure 33. Hence, the racaemic epoxide 106 2642
2590 this group decided to modify the ADH from was opened using whole cells of Yarrowia lipolytica 2643
2591 Thermoethanolicus brockii (TbSADH, slightly (R)-select- containing epoxide hydrolase activity, and the non- 2644
2592 ive (23% ee) at full conversion) by genetic engineering, converted substrate (S)-106 (20% yield, 97.8% ee) was 2645
2593 using triple-code saturation mutagenesis (TCSM), chemically opened leading to halohydrin (S)-108, 2646
2594 obtaining highly (R)- and (S)-selective variants (62–94% which upon a lipase-catalyzed hydrolysis and acid 2647
2595 ee for (S)-selective, 95%99% ee for (R)-slective) with catalysis furnished (S)-103 with moderate yields (79%), 2648
2596 minimal screening at semipreparative scale (Sun et al. not altering the good enantioselectivity obtained in 2649
2597 2016). the preparation of starting (S)-106. 2650
2651 2704
2652 2705
2653 2706
2654 2707
2655 2708
2656 2709
2657 2710
2658 2711
2659 2712
2660 2713
2661 2714
2662 2715
2663 2716
2664 2717
2665 2718
2666 2719
2667 2720
2668 2721
2669 2722
2670 2723
2671 2724
2672 2725
2673 2726
2674 2727
2675 2728
2676 2729
2677 2730
2678 2731
2679 Figure 33. Some biocatalyzed methods for obtaining (S)-tetrahydrofuran-3-ol (S)-103. 2732
2680 2733
2681 11b-hydroxysteroid dehydrogenase Type 1 (11b- in this area, developing many different chemical struc- 2734
2682 HSD1) inhibitors tures displaying inhibition of 11b-HSD1 (Scott et al. 2735
2683 2014); many of these chemical structures present ster- 2736
2684 An increased abnormal concentration of glucocorti- 2737
eogenic centres, and thus they could be synthesized
2685 coids (GCs) may lead to its precipitation, with the con- 2738
with the help of biocatalysis. We will show only some
2686 comitant aggravation of truncal obesity, insulin 2739
examples covering this field, being the first one oxazo-
2687 resistance, hepatic triacylglycerol accumulation, hyper- 2740
glycaemia, hypertension and dyslipidaemia. This is lone 112 (Figure 34) reported by Biovitrum, having
2688 2741
known as metabolic syndrome (Grundy et al. 2004), reasonable potency tested in vitro (Sutin et al. 2007).
2689 2742
and it represents a major risk factor for Type 2 DM and Preparation of the chiral amine (S)-111, required for
2690 2743
cardiovascular disease. Thus, interventions to reduce synthesizing 112, has been recently described by
2691 2744
GC action can prevent and reverse these effects. One Martinez-Montero and coworkers, by means of a trans-
2692 2745
of the most important enzymes involved in GCs activ- amination of the corresponding ketone 110, in high
2693 2746
ity is 11b-hydroxysteroid dehydrogenase 1 (11b-HSD1), yield (95% conversion) and stereoselectivity (>99% ee)
2694 2747
which converts cortisone to cortisol, the primary GC in (Martinez-Montero et al. 2017).
2695 2748
humans, mostly in liver and adipose tissue, so that the In another example, monoester 114, required for
2696 2749
2697 inhibition of this enzyme could reduce cortisol produc- preparing the 11b-HSD1 inhibitor 115 (Peddi et al. 2750
2698 tion within these tissues without substantially affecting 2010), has been prepared starting from diester 113, by 2751
2699 circulating cortisol (Anderson and Walker 2013). This is using a lipase catalyzed mono-hydrolysis, not continu- 2752
2700 the reason why 11b-HSD1 has been proposed as an ing to the diacid (Guo et al. 2014). Thus, about 100 kg 2753
2701 innovative therapeutic target for the treatment of of 114 were prepared in 78% yield by hydrolysis of 2754
2702 Type 2 DM (Bailey et al. 2016; Bailey 2017). There are 113 with a commercially available lipase from 2755
2703 many pharmaceutical companies working very actively Burkholderia cepacia: a more efficient enzymatic 2756
2757 2810
2758 2811
2759 2812
2760 2813
2761 2814
2762 2815
2763 2816
2764 2817
2765 2818
2766 2819
2767 2820
2768 2821
2769 2822
2770 2823
2771 2824
2772 Figure 34. Biocatalytic procedures for preparing some 11b-HSD1 inhibitors. 2825
2773 2826
2774 2827
2775 2828
2776 2829
2777 2830
2778 2831
2779 2832
2780 2833
2781 2834
2782 2835
2783 2836
2784 2837
2785 2838
2786 2839
2787 2840
2788 2841
2789 2842
2790 2843
2791 2844
2792 2845
2793 2846
2794 Figure 35. Some 11b-HSD1 inhibitors possessing an adamantyl moiety in their structures. 2847
2795 2848
2796 2849
2797 2850
2798 process was developed for the hydrolysis of 113 that 120 (Venier et al. 2011), developed by Sanofi, are at 2851
2799 gave the monoester 114 in 82% yield using signifi- different levels of clinic assays. 2852
2800 cantly lower amounts of the commercially available Microbial oxidation of adamantane 121 (Figure 36) 2853
2801 immobilized lipase B from C. antarctica. is a good alternative for obtaining hydroxylated deriv- 2854
2802 As we commented before, there are many pharma- atives, because chemical methods require harsh 2855
2803 ceutical companies working very actively in the prep- oxidants, are poorly selective and are prone to overox- 2856
2804 aration of 11b-HSD1 inhibitors; many of the candidates idation; subsequently, these hydroxylated derivatives 2857
2805 present an adamantyl moiety in its structure, as shown can be chemically converted in other structures 2858
2806 in Figure 35. In fact, compounds such as 116, from required for the preparation of those drug candidates 2859
2807 Pfizer (Cheng et al. 2010); 117 (Scott et al. 2012a) and presented before. 2860
2808 118 (Scott et al. 2012b), from AstraZeneca; 119 Biohidroxylation of 121 catalyzed by Streptomyces 2861
2809 (Becker et al. 2008; An et al. 2013) from Abbott, or griseoplanus was described by Mitsukura and 2862
2863 2916
2864 2917
2865 2918
2866 2919
2867 2920
2868 2921
2869 2922
2870 2923
2871 2924
2872 2925
2873 2926
2874 2927
2875 2928
2876 2929
2877 2930
2878 2931
Figure 36. Microbial hydroxylation of adamantane and derivatives.
2879 2932
2880 2933
coworkers in 2006: among 470 strains tested, S. griseo- The focus has been centred in the different types of
2881 2934
planus was highly regioselective to give 1-adamanta- drugs actually being used, and we have not considered
2882 2935
nol 122 in 32% molar conversion yield after 72-h the effect of combined drugs (a very common thera-
2883 2936
cultivation in the presence of 3% (v/v) Tween 60. peutic strategy), because this is out of the aim of this
2884 2937
This same group also described the production of revision. According to the market volume of these
2885 2938
1,3-adamantanediol 123 by a regioselective monohy- types of drugs, we can foresee a clear increase in the
2886 2939
droxylation of 122 using Streptomyces sp. SA8, produc- use of versatile biocatalyzed protocols for the produc-
2887 2940
ing 5.9 g L1 of 123 starting from 6.2 g L1 of 122 in tion of antidiabetic drugs.
2888 2941
culture broth after 120 h at 25 C (Mitsukura et al.
2889 2942
2010). Using resting cells, 2.3 g L1 of 122 was pro-
2890 2943
duced after 96 h of incubation at a 69% conversion Acknowledgements
2891 2944
rate. In both cases, 1,4-adamantanediol 124 was The author would like to give special thanks to the library of
2892 2945
formed as a byproduct at a rate of about 15%; this the Faculty of Pharmacy for the technical help in finding and
2893 2946
strain SA8 was also able to hydroxylate 2-adamantanol management of scientific literature used for this review.
2894 2947
2895 and 2-methyl-2-adamantanol. Similarly, washed cells 2948
2896 (62 mg) of Kitasatospora sp. GF12 in 4 mL buffer (pH 7) 2949
were used for catalyzing the regioselective hydroxyl- Disclosure statement
2897 2950
2898 ation of 60 mM 123 to 30.9 mM 1,3,5-adamantanetriol The author reports no declarations of interest. 2951
2899 125 over 120 h at 24 C (Mitsukura et al. 2012), adding 2952
2900 glycerol (400 mM) to the reaction mixture to recycle 2953
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Alcantara 2018 Biocatalyzed Synthesis of Antidiabe

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Author(s): Cristina M. Alc

Article title: Biocatalyzed synthesis of antidiabetic drugs: A review

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