N-​[(7S)-​1,​2,​3,​10-​tetramethoxy-​9-​oxo-​5,​6,​7,​9​tetrahydrobenzo​[a]​heptalen-​7-​yl]​acetamide

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Colchicine Systematic (IUPAC) name N-​[(7S)-​1,​2,​3,​10-​tetramethoxy-​9-​oxo-​5,​6,​7,​9​tetrahydrobenzo​[a]​heptalen-​7-​yl]​acetamide
CAS number 64-86-8

A major alkaloid from Colchicum autumnale L. and found also in other Colchicum species. Its primary therapeutic use is in the treatment of gout, but it has been used also in the therapy of familial Mediterranean fever (periodic disease)

Identifiers
CAS number ATC code PubChem IUPHAR ligand DrugBank ChemSpider UNII KEGG ChEBI ChEMBL Formula Mol. mass SMILES 64-86-8 M04AC01 CID 6167 2367 DB01394 5933 SML2Y3J35T D00570 CHEBI:27882 CHEMBL107 Chemical data C22H25NO6 399.437 eMolecules & PubChem

Oral colchicine has been used for many years as an unapproved drug with no prescribing information, dosage recommendations, or drug interaction warnings approved by the U.S. Food and Drug Administration (FDA).[2] On July 30, 2009 the FDA approved colchicine as a monotherapy for the treatment of three different indications: familial Mediterranean fever, acute gout flares, and for the prophylaxis of gout flares,[2] and gave URL Pharma a three-year marketing exclusivity agreement[3] in exchange for URL Pharma doing 17 new studies and investing $100 million into the product, of which $45 million went to the FDA for the application fee. URL Pharma raised the price from $0.09 per tablet to $4.85, and the FDA removed the older unapproved colchicine from the market in October 2010 both in oral and IV form, but gave pharmacies the opportunity to buy up the older unapproved colchicine.[4] Colchicine in combination with probenecid has been FDA approved prior to
1982.[3]

References ^ a b "Colchicine for acute gout: updated information about dosing and drug interactions". National Prescribing Service. 14 May 2010. Retrieved 14 May 2010. ^ a b "FDA Approves Colchicine With Drug Interaction and Dose Warnings". July 2009. ^ a b [1] FDA Orange Book; search for colchicine ^ Questions and Answers for Patients and Healthcare Providers Regarding Single-ingredient Oral Colchicine Products

Several experiments have shown that the biosynthesis of colchicine involves the amino acids phenylalanine and tyrosine as precursors. Indeed, the feeding of Colchicum autumnale with radioactive amino acid, tyrosine-2-C14, caused the latter to be partially incorporated in the ring system of colchicine. The induced absorption of radioactive phenylalanine-2-C14 by Colchicum byzantinum, another plant of the Colchicaceae family, resulted in its efficient absorption by colchicine.[19] However, it was proven that the tropolone ring of colchicine resulted, in essence, from the expansion of the tyrosine ring. Further radioactive feeding experiments of Colchicum autumnale revealed that Colchicine can be synthesized biosynthetically from (S)-Autumnaline. That biosynthesic pathway occurs primarily through a para-para phenolic coupling reaction involving the intermediate isoandrocymbine. The resulting molecule undergoes Omethylation directed by S-Adenosylmethionine (SAM). Two oxidation steps followed by the cleavage of the cyclopropane ring leads to the formation of the tropolone ring contained by N-formyldemecolcine. Nformyldemecolcine hydrolyzes then to generate the molecule demecolcine, which also goes through an oxidative demethylation that generates deacetylcolchicine. The molecule of colchicine appears finally after addition of acetyl-Coenzyme A to deacetylcolchicine.,[20][21]

Colchicine inhibits microtubule polymerization by binding to tubulin, one of the main constituents of microtubules. Availability of tubulin is essential to mitosis, and therefore colchicine effectively functions as a "mitotic poison" or spindle poison.[10] The mitosis inhibiting function of colchicine has been of great use in the study of cellular genetics. To see the chromosomes of a cell under a light microscope, it is important that they be viewed near the point in the cell cycle in which they are most dense. This occurs near the middle of mitosis, so mitosis must be stopped before it completes. Adding colchicine to a culture during mitosis is part of the standard procedure for doing karyotype studies. Apart from inhibiting mitosis (a process heavily dependent on cytoskeletal changes), colchicine also inhibits neutrophil motility and activity, leading to a net anti-inflammatory effect.

3.コルヒチンの生合成 コルヒチン(Colchicine)はユリ科イヌサフランに含まれ、トロポロン(tropolone)骨格を 有する珍しい構造をもつ含窒素化合物である。3環性でありながら窒素原子が環の中に 含まれない非複素環化合物であり、しかもアミドであるため塩基性を示さない。典型的な アルカロイドには見えないが、生合成的見地からすればコルヒチンは純然たる真正アル カロイドの1種である。標識化合物を用いた投与実験で、コルヒチンのA環部およびC-5、 C-6、C-7はフェニルアラニンに由来することが明らかにされている。その結果、コルヒ チンのユニークな基本骨格は図4に示すようにドーパミン(またはチラミン)とケイヒ酸が 縮合してできるフェネチルイソキノリンが酸化カップリング、転位、環拡大反応を経て生 合成されると推定されている。この生合成スキームで中間体とされるフェネチルイソキノ リン誘導体アウタムナリン(Autamnaline)はイヌサフランの同属近縁種Colchicum cornigerumから実際に単離されている。ベンジルイソキノリンアルカロイドが比較的広 く分布するのに対してコルヒチンなどフェネチルイソキノンアルカロイドは天然界では極 めて稀な存在である。 イヌサフランの種子は欧州において17世紀から通風治療に用いられていたが、その 活性成分としてコルヒチンが単離されたのは1886年のことであった。コルヒチンは今日 でも抗通風薬として用いられるが、その他、細胞分裂において紡錘糸の形成を阻害する というユニークな生物活性が知られている。一方で染色体分裂は阻害しないので、コル ヒチン処理により倍数体の細胞ができる。これを利用して農業分野において種なし果実 などをつくるのに利用されている。

Colchicine (Colchicine) is the lily family dog saffron is included in, which is a nitrogen-containing compound having a skeleton with an unusual structure (tropolone) tropolone. Is a non-heterocyclic compounds that are not included in the nitrogen atom in the ring yet ring of 3, do not show because it is a basic amide addition. The typical alkaloid is not visible, colchicine is pure from the standpoint of biosynthesis genuine alkaloid which is a kind of.In the experiment using the labeled compound administration, C-5, C-6, C-7 can be derived from phenylalanine has been found to part and the A ring of colchicine. As a result, the basic skeleton unique colchicine Figure 4 is biosynthesized through oxidative coupling, dislocation phenethyl isoquinoline can be fused cinnamic acid and (tyramine) or dopamine, as shown in, the ring-expansion reaction has been estimated. (Autamnaline) actually have been isolated from related species of genus Colchicum cornigerum dog saffron Autamunarin phenethyl isoquinoline derivatives that are intermediates in this biosynthetic scheme. Phenethyl isoquinone in the world of natural alkaloids such as colchicine is extremely rare is the presence as opposed to a relatively wide distribution benzyl isoquinoline alkaloid. Saffron seeds of dogs have been used to treat ventilation from the 17th century in Europe, it was isolated colchicine as the active ingredient of which was that of 1886. Colchicine is used as an anti-drug ventilation Even today, other unique biological activity, that inhibit the formation of spindle fibers in cell division are known. Chromosome division because it does not inhibit the other hand, can be of polyploid cells by colchicine treatment. Has been used to make, such as seedless fruit in the field of agriculture to take advantage of this

This paper presented a very neat use of RCM and quite clever strategy to construct the 7,7-fused core of colchicine. For the first time, the 7,7-fused bicyclic system could be accessed very quickly in a single step. This main strategy is summarized in the retrosynthetic analysis below.

http://pubs.acs.org/doi/abs/10.1021/ ol070708j

The key reactions were formylation of 6 mediated by SnCl4 to give 7and the synthesis of propargylic alcohol 14 which was achieved in three steps from 5, using the Ohira-Bestman reagent in the last step. Next, sequential RCM reactions were performed on 14 using Grubbs' second generation catalyst (15) after the protection of the OH group with TMS. The reaction proved to be very efficient, providing the desired 16 in 74% yield from 14.

This intermediate 16 was further elaborated as shown in Scheme 4 via oxidative rearrangement.
Compound 18 could be obtained in high yield. However, going along a more well-known route of previous total syntheses of colchicine, intermediate 19 could be obtained in modest yield, along with 20, from 17. This latter route effectively constituted a formal synthesis of colchicine. The final completion of this molecule by a novel sequence is currently under investigation

The plant source of colchicine, the autumn crocus (Colchicum autumnale), was described for treatment of rheumatism and swelling in the Ebers Papyrus (ca. 1500 B.C.), an Egyptianmedical papyrus.[5] The use of the bulb-like corms of Colchicum for gout probably traces back to ca. 550 A.D., as the "hermodactyl" recommended by Alexander of Tralles. Colchicum extract was first described as a treatment for gout in De Materia Medica by Pedanius Dioscorides in the first century CE. Colchicum corms were used by the Persian physician ibn Sina (Avicenna) and other Islamic physicians, were recommended by Ambroise Pare in the sixteenth century, and appeared in the London Pharmacopoeia of 1618. Colchicum plants were brought to Americaby Benjamin Franklin, who suffered from gout himself and had written humorous doggerel about the disease during his stint as Envoy to France.

FT-IR spectra of Colchicine (4000-400) cm-1

FT-Raman spectra of Colchicine (4000-100) cm-1

KEGG DrugD00570 KEGG CompoundC07592 PubChem Compound6167 PubChem Substance46505639 ChemSpider5933 ChEBI233 59 ChEMBL23359 Therapeutic Targets DatabaseDAP001254 PharmGKBPA449092 IUPHA R2367 Guide to Pharmacology2367 HETLOC Drug Product Database396 RxListhttp://www.rxlist.com/cgi/ge neric/colch.htm Drugs.comhttp://www.drugs.co m/cdi/colchicine.html Wikipediahttp://en.wikipe dia.org/wiki/Colchicine

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