(4) Isoquinoline

Isoquinoline is a heterocyclic aromatic organic compound. It is a structural isomer

of quinoline. Isoquinoline is a colorless hygroscopic liquid at room temperature
with a penetrating, unpleasant odor. The Biosynthetic origin (Amino Acids) of
Isoquinoline is (Phenilalanine, tyrosine + C10).
This family is divided into subgroups Like: Benzyl isoquinoline ,Bisbenzyl
isoquinoline and d-Tubocurarine (Curare). And Mescaline, Hydrastine,
phthalideisoquinoline.
Also, there is Commonly Alkaloids Among Isoquinolines like Berberine, Boldine,
Chelidonine, Galanthamine, Papaverine, Sanguinarine. And morphine, codeine,
and thebain which are all alkaloids of opium.

Structure
Isoquinolines in general are composed of a benzene ring fused to a pyridine ring.
Which has a molecular formula (C9H7N) that Isoquinoline and quinoline are
benzopyridines.
Specifically, in Isoquinoline Alkaloids, Bisbenzyl isoquinolinevwhich represented
as (liensinine, neferine, and isoliensinine). structurally constructed of two
monomeric benzylisoquinoline units joined by one or more ether bridges that has
molecular formula (C23H19N). And Tubocurarine like D-Tubocurarine is a toxic
alkaloid which has a Molecular Formula (C37H41N2O6+).

Also, Benzylisoquinoline that this subgroup has a molecular formula (C16H13N)

is exemplified in these compounds: papaverine, noscapine, codeine, morphine,
berberine. Berberine is a quaternary ammonium salt from the protoberberine group
of benzylisoquinoline alkaloids.
Plant Origin
We can find Isoquinoline widely distributed among plants coming from poppy
family (Papaveraceae) like Glaucium flavum Crantz—yellow horned poppy,
Papaveraceae Herb and apaver somniferum L.–Opium poppy, Papaveraceae
Opium where they are mostly present in the form of tetrahydro-bases,
Berberidaceae, Fumariaceae, Menispermaceae, Ranunculaceae, Rutaceae in
general. A few plant species which belong to the Magnoliaceae and
Convolvulaceae are also rich in these alkaloids and Carapichea ipecacuanha in
Rubiaceae family.1
To be more specific, Benzylisoquinoline found from tyrosine in the Papaveraceae,
Berberidaceae as a plant source and Opium poppy (Papaver somniferum), Like
California poppy for the narcotic analgesic’s morphine, codeine.2
Berberine found in many plants as Berberis, such as Berberis vulgaris (barberry),
Berberis aristata (tree turmeric), Mahonia aquifolium (Oregon grape), Hydrastis
canadensis (goldenseal), Xanthorhiza simplicissima (yellowroot), Phellodendron
amurense (Amur cork tree).

But Bisbenzyl isoquinoline Origin plants of the families are Berberidaceae,

Menispermaceae and Ranunculaceae, Aristolochiaceae, Annonaceae, Buxaceae,
Lauraceae.3

Curare Alkaloids include the tree kinds (Para, Tube or Bamboo Curare) from
Brazilian Menispermacese like Abuta selloana, and Chondrodendron tomentosum
and the Loganiaceae and Strychnos toxifera. 4 specifically D-Tubocurarine that
naturally occurring mono-quaternary alkaloid found in the bark of the
Menispermaceous South American plant.
Biosynthesis
1
https://www.sciencedirect.com/topics/neuroscience/isoquinoline-alkaloid
2
Hagel, Jillian M., and Peter J. Facchini. "Benzylisoquinoline alkaloid metabolism: a century of discovery
and a brave new world." Plant and Cell Physiology 54.5 (2013): 647-672. doi:10.1093/pcp/pct020
3
P. L. SchiffJr., Bisbenzylisoquinoline Alkaloids In: Phillipson J.D., Roberts M.F., Zenk M.H. (eds) The Chemistry and
Biology of Isoquinoline Alkaloids. (1985), Page: 126-127
4
HOMAS ANDERSON HENRY D.Sc.(Lond.), THE PLANT ALKALOIDS, Fourth edition, (1949), Page: 373
Tubocurarine biosynthesis of alkaloids involves a radical coupling of the two
enantiomers of N-methylcoclaurine. (R) and (S)-N-methylcoclaurine come from a
Mannich-like reaction between dopamine and 4-hydroxyphenylacetaldehyde,
facilitated by norcoclaurine synthase (NCS). Both dopamine and 4-
hydroxyphenylacetaldehyde originate from L-tyrosine. Methylation of the amine
and hydroxyl substituents are facilitated by S-adenosyl methionine (SAM). One
methyl group is present on each nitrogen atom prior to the radical coupling. The
additional methyl group is transferred to form tubocurarine, with its single
quaternary N,N-dimethylamino group.5

Papaverine Biosynthesis route was initially the N-demethylation pathway starting

from (S)-reticuline as supported by a recent radio tracer study, and the (S)-
coclaurine-derived pathway, supported by comparative transcriptome evidence.
Only three enzymes of the proposed routes have been identified and characterized,
namely 7OMT in the N-demethylation pathway, N7OMT in the (S)-coclaurine-
derived pathway, and an oxidase catalyzes the last step shared by both routes6.

5
Dewick, P. M. Medicinal Natural Products; a Biosynthetic Approach. 3rd ed.; John Wiley and Sons Ltd.: 2009
6
Han, Xu, et al. "The biosynthesis of papaverine proceeds via (S)-reticuline." Phytochemistry 71.11-12
(2010): 1305-1312. doi:10.1016/j.phytochem.2010.04.022
Berberine biosynthesis start with (S)-reticuline is converted to (S)-scoulerine by
the action of a well-characterized flavin-dependent enzyme, berberine bridge
enzyme. This enzyme has been cloned from several plant species, and the
mechanism of this enzyme has been studied extensively. (S)-scolerine is then O-
methylated by scoulerine 9-O-methyltransferase to yield (S)-
tetrahydrocolumbamine. Heterologous expression of this gene in E. coli yielded an
enzyme that had the expected substrate specificity. A variety of O-methyl
transferases also have been cloned from Thalictrum tuberosum (30). The substrate-
specific cytochrome P450 oxidase canadine synthase that generates the methylene
dioxy bridge of (S)-canadine has been cloned recently. The final step of berberine
biosynthesis is catalyzed by a substrate-specific oxidase, tetrahy-
droprotoberberine oxidase7.

Medical Application
There are many Medical applications of Isoquinoline Alkaloids.
Starting with Berberine Alkaloid, that has anti-inflammatory properties, which
means that it could help treat diabetes and other inflammation-related health
conditions8. Also, berberine could delay the onset of high blood pressure and,
when it did develop, help reduce its severity9.Berberine can create changes
within the molecules of cells, and this could have another potential benefit in
fighting cancer. Because berberine, has “clear inhibitory effects” on these
types of cancers: colorectal cancer, lung cancer, ovarian cancer, prostate
cancer, liver cancer10.
Moving to Morphine Alkaloid, first, is used to help relieve moderate to severe
pain. Morphine belongs to a class of drugs known as opioid (narcotic)
analgesics as advanced tools for chemical therapy, such as anticancer,
antidiabetes, and antimalarial drugs. It works in the brain to change how your

7
doi: 10.1002/9780470048672.wecb004
8
Liu, Yucheng, et al. "Inhibition of JNK by compound C66 prevents pathological changes of the aorta in
STZ‐induced diabetes." Journal of cellular and molecular medicine 18.6 (2014): 1203-1212.
doi:10.1155/2014/289264
9
Guo, Zhentao, et al. "Anti-hypertensive and renoprotective effects of berberine in spontaneously
hypertensive rats." Clinical and Experimental Hypertension 37.4 (2015): 332-339.
doi:10.3109/10641963.2014.972560
10
A Natural Isoquinoline Alkaloid With Antitumor Activity: Studies of the Biological Activities of Berberine, 2019,
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382680/
body feels and responds to pain11. Also, Morphine is beneficial in reducing the
symptom of shortness of breath due to both cancer and noncancer causes. In
the setting of breathlessness at rest or on minimal exertion from conditions
such as advanced cancer or end-stage cardiorespiratory diseases, regular,
low-dose sustained-release morphine significantly reduces breathlessness
safely, with its benefits maintained over time12.
Bisbenzyl isoquinoline in general used for arthritis, heat-clearing and
detoxification, ulcers, and carbuncles13. Also, compromised the depolymerization
of microtubules and impaired mitochondrial and endoplasmic reticulum function in
human breast adenocarcinoma 14.

Anther isoquinioline alkaloid is Tubocurarine, Tubocurarine is used in

anesthesiology as a myorelaxant, causing prolonged muscle relaxation during the
operations. Also, one of the Tubocurarine derivatives Tubocurarine chloride It can
be used in treating vascular disorders. Tubocurarine acts as a competitive inhibitor
in the nicotinic acetylcholine receptor, that the nerve impulse is blocked by this
alkaloid. Tubocurarine is used in surgical practice as a muscle relaxant15.
Also, Isoquinoline alkaloids as liriodenine used as therapy for Parkinson's
disease.16

Chemical Tests

11
James H. Beaty, James R. Kasser, Rockwood and Wilkins' Fractures in Children, Lippincott Williams &
Wilkins, 2010, Page: 54
12
Abdallah, Sara J., et al. "Effect of morphine on breathlessness and exercise endurance in advanced
COPD: a randomised crossover trial." European Respiratory Journal 50.4 (2017): 1701235.
Doi: 10.1183/13993003.01235-2017
13
https://www.sciencedirect.com/topics/neuroscience/bisbenzylisoquinoline-alkaloid
14
https://doi.org/10.1016/B978-0-12-814232-5.00003-4
15
https://www.sciencedirect.com/topics/neuroscience/tubocurarine-chloride
16
Niwa T., Kajita M., Nagatsu T. (1998) Isoquinoline Derivatives. In: Moser A. (eds) Pharmacology of
Endogenous Neurotoxins. Birkhäuser, Boston https://doi.org/10.1007%2F978-1-4612-2000-8_1
Usually we use different tests vary in the reagents and the alkaloids that we want
test and analysis it. So, the following is many examples of many alkaloids and the
chemical tests.
We use chromic acid reagent for Berberine and a crystallization will form which
shaped moss-like or fine needles, often in rosettes.17
For Papaverine we use Potassium Hydroxide Reagent as a chemical test that
Amorphous precipitates appear in the solution and these precipitates all crystallize
on standing and crystallization takes place more slowly in the more concentrated
solutions. The crystals are small rods or rosettes of rods often arranged in the shape
of fan-like stars. Upon adding this reagent to a 1: 10,000 solution and stirring, a
considerable number of small rods are formed at once. Potassium chromate and
give results similar to the above.18

Moving to Morphine, the best test for morphine Marme’s Reagent in all the
solutions except the 1: 1000 a gelatinous precipitate is formed which crystallizes
out quickly. This precipitate has a silvery appearance under the microscope. These
crystals are rosettes of very fine needles and are characteristic. They form a dense
mass, especially so in the more concentrated solutions. In the 1: 1000 solution we
get no precipitate, but by adding a drop of the reagent and allowing to stand for a
short time, long needles form around the edge of the drop.
And we use Wagner’s Reagent for Morphine A very characteristic test which a
heavy, amorphous precipitate is formed in all solutions. This precipitate forms
reddish-brown drops before crystallization takes place, and from the precipitate,
crystallization takes place very slowly. It is often necessary to allow the solution to
stand several minutes before crystals are formed. The crystals are large plates,
reddish-brown in color, and irregular in outline. Optimum concentration is about 1:
200.19

17
tephenson, Charles Henry, and Charles Edwin Parker. Some Microchemical Tests for Alkaloids. JB Lippincott,
1921 Page: 15/24
18
tephenson, Charles Henry, and Charles Edwin Parker. Some Microchemical Tests for Alkaloids. JB Lippincott,
1921 Page: 62
19
tephenson, Charles Henry, and Charles Edwin Parker. Some Microchemical Tests for Alkaloids. JB Lippincott,
1921 Page: 55-56
In case of Codeine Alkaloid, we use Marme's Reagent, it’s the best test for
Codeine as Morphine. First, we have an amorphous precipitate and from this great
number of small, silvery-appearing masses are formed at once especially in the
more concentrated solutions, such as the 1: 200 solution, these masses start to
crystallize and crystallization spreads rapidly over the field and the crystals appear
as small rods in masses20.

Also, we use Chromic Reagent for Codeine which the amorphous precipitate first
formed quickly changes into oil-like drops. Crystals are formed only in the 1: 50
solution. They are characteristic, dark in appearance, and are normally spherical, or
rosettes of plates. Sometimes they are much larger and bushy in appearance. The
formation of crystals takes place slowly unless the drop be stirred.

Also, Isoquinoline alkaloids can be characterized by the Radulescu’s test (chemical

test). In addition to the usual precipitation reactions, morphine gives a blue color
with ferric chloride. When a dilute solution of morphine is treated with nitrous acid
and the solution then made alkaline with a solution of ammonia, an orange-brown
color is produced. This is Radulescu’s test and is the basis of the colorimetric
determination of small amounts of morphine.
But d-tubocurarine from Tube curare and from Pareira brava root and the alkaloids
occurring in Ipecacuanha root. Ipecacuanha contains the phenolic alkaloids
cephaeline and psychotrine, and the nonphenolic alkaloids methyl psychotrine and
emetine. The latter is the most important and can be extracted with difficulty with
acids and may be oxidized to give an orange-red-colored compound.21

20
tephenson, Charles Henry, and Charles Edwin Parker. Some Microchemical Tests for Alkaloids. JB Lippincott,
1921 Page: 41
21
K. Paech, M. V. Tracey, Modern Methods of Plant Analysis / Moderne Methoden der Pflanzenanalyse: Volume 4
Volume 4 of Modern Methods of Plant Analysis Moderne Methoden der Pflanzenanalyse , Springer Science &
Business Media, 2013, Page: 454