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Duocarmycin analogues

Structural formula of Duocarmycin
Duocarmycin A

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 and CC-1065, represent a class of highly potent antineoplastic compounds.[1][2]  Duocarmycins and CC-1065 are members of this small group of DNA minor groove, AT-sequence selective, and adenine-N3 alkylating agents, isolated from Streptomyces sp. exhibiting extremely potent cytotoxicity against the growth of cancer cells grown in culture. Notable for their extreme cytotoxicity they represent a class of exceptionally potent antitumour antibiotics. [3]

Initial synthesis and structural modification of the cyclopropa[c]pyrrolo[3,2-e]indole (CPI) DNA-alkylating motif as well as the indole non-covalent binding region in the 1980s have led to a number of compounds that entered clinical trials as potential anticancer drugs. However, due to significant systemic toxicity these analogs have not passed clinical evaluation as single agents.  Because of

Solid tumors
Duocarmycins and CC-1065 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.

CC-1065  is a potent antitumor antibiotic produced by Streptomyces zelensis, which interacts strongly with double-stranded DNA and appears to exert its cytotoxic effects through disruption of DNA synthesis. Studies have shown that CC-1065 is one of the most cytotoxic agents known. The concentrations required for a 50 and 90% inhibition of cell growth are 0.02 and 0.05 ng/ml, respectively. It is about 400 times more cytotoxic than was Adriamycin. The action of CC-1065 is rapid and is dose and time dependent. CC-1065 inhibits DNA synthesis much more than it inhibits RNA and protein synthesis. The concentrations required for a 50% inhibition of DNA synthesis and RNA synthesis are 4 to 6 and 45 to 60 ng/ml, respectively.

Site exclusion studies using substitutions in the DNA grooves have shown that CC-1065 to bind primarily in the minor groove. In these studies CC-1065 did not cause DNA breaks; it inhibited susceptibility of DNA to nuclease S1 digestion. It raised the thermal melting temperature of DNA, and it inhibited the ethidium-induced unwinding of DNA. Thus, in contrast to many antitumor agents, CC-1065 stabilized the DNA helix. DNA helix overstabilization may be relevant to the mechanism of action of CC-1065.

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

See: ADC Review / Knowledge Center

[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. <br>
[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</br>
[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.<br>

Last Editorial Review: March 7, 2015

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