Duocarmycin analogues

Chemical Name: 1,2,4,5,8,8a-hexahydro-4-oxo-2-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl)]-cyclopropa[c]pyrrolo[3,2-e]indole-6-carboxylic acid methyl ester, (+)-duocarmycin SA, duocarmycin SA, antibiotic DC 113

Molecular Weight: 477.47

Formula: C25H23N3O7

CAS#: 130288-24-3

Solubility: Sparingly Soluble (0.030 g/L) (25 ºC), Calc.*

Density: 1.53±0.1 g/cm3 (20 ºC 760 Torr), Calc.*

Formula shown: Duocarmycin A

Biological Activity
Analogues of naturally occurring antitumour agents, such as duocarmycins, represent a new class of highly potent antineoplastic compounds.[1][2]

Duocarmycins are members of a small group of natural products that are notable for their extreme cytotoxicity and thus represent a class of exceptionally potent antitumour antibiotics. [3] They are small-molecule, synthetic, DNA minor groove binding alkylating agents suitable to target solid tumors - this means that they bind to the minor groove of DNA and subsequently cause irreversible alkylation of DNA. This disrupts the nucleic acid architecture, which eventually leads to tumor cell death.

Duocarmycins are able to exert their mode of action at any phase in the cellular cycle, whereas tubulin binders will only attack tumor cells when they are in a mitotic state. Growing evidence suggests that DNA damaging agents, such as duocarmycins, are more efficacious in tumor cell killing than tubulin binders, particularly in case of solid tumors.

Duocarmycins, which were  first isolated from Streptomyces bacteria in 1988, have shown activity in a variety of multi-drug resistant (MDR) models. Agents that are part of this class of duocarmycins have the potency in the low picomolar range. This makes them suitable for maximizing the cell-killing potency of antibody-drug conjugates to which they are attached.

Another important benefit is that, unlike other drug classes, duocarmycins can be effective against tumor cells that are multi-drug resistant. For example, potent cytotoxicity has been demonstrated in cells that express the P-glycoprotein (P-gp) efflux pump. Multi-drug resistance presents a significant problem in the clinical setting and agents that are less susceptible to these mechanisms can successfully be used in prolonged treatment protocols. 

Reference:
[1] Tietze LF, Krewer B. Antibody-directed enzyme prodrug therapy: a promising approach for a selective treatment of cancer based on prodrugs and monoclonal antibodies. Chem Biol Drug Des. 2009 Sep;74(3):205-11. doi: 10.1111/j.1747-0285.2009.00856.x. Epub 2009 Jul 29.
[2] Cacciari B, Romagnoli R, Baraldi PG, Da Ros T, Spalluto G. CC-1065 and the duocarmycins: recent developments. Expert Opinion on Therapeutic Patents 2000, December 10 (12) :1853-71 doi:10.1517/13543776.10.12.1853
[3] Tercel M, McManaway SP, Leung E, Liyanage HD, Lu GL, Pruijn FB. The cytotoxicity of duocarmycin analogues is mediated through alkylation of DNA, not aldehyde dehydrogenase 1: a comment. Angew Chem Int Ed Engl. 2013 May 17;52(21):5442-6. doi: 10.1002/anie.201208373. Epub 2013 Apr 24.

* Calculated using Advanced Chemistry Development (ACD/Labs) Software V11.02 (©1994-2014 ACD/Labs)

This page was last updated on October 30, 2013.

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