Anthony crasto presents colchinine review

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

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6. 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)

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

8. 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]

9. 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

10.  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 O-
methylation 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. N-
formyldemecolcine 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]

12.  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.

13. 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。

14.  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 iso-
quinone 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

16. 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

19. 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.

21. 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

23.  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.

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

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

33.  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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37. DR ANTHONY MELVIN CRASTO Ph.D
amcrasto@gmail.com
MOBILE-+91 9323115463
GLENMARK SCIENTIST , NAVIMUMBAI, INDIA
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