The duocarmycins are members of a series of related
natural products first isolated from Streptomyces bacteria in 1978.[1][2][3] They are notable for their extreme cytotoxicity and thus represent a class of exceptionally potent antitumour antibiotics.[4][5]
Biological activity
As small-molecule, synthetic, DNA minor groove binding alkylating agents, duocarmycins are suitable to target solid tumors. They bind to the
minor groove of DNA and
alkylate the nucleobase
adenine at the N3 position.[6][7] The irreversible alkylation of DNA disrupts the nucleic acid architecture, which eventually leads to tumor cell death. Analogues of naturally occurring antitumour agents, such as duocarmycins, represent a new class of highly potent antineoplastic compounds.[8][9]
The work of
Dale L. Boger and others created a better understanding of the
pharmacophore and
mechanism of action of the duocarmycins. This research has led to synthetic analogs including
adozelesin,
bizelesin, and
carzelesin which progressed into clinical trials for the treatment of cancer. Similar research that Boger utilized for comparison to his results involving elimination of cancerous tumors and antigens was centered around the use of similar immunoconjugates that were introduced to cancerous colon cells. These studies related to Boger's research involving antigen-specificity that is necessary to the success of the duocarmycins as antitumor treatments.[10]
Duocarmycin analogues vs tubulin binders
The duocarmycin 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.[11]
Duocarmycins
Duocarmycin A
Duocarmycin B1
Duocarmycin B2
Duocarmycin C1
Duocarmycin C2
Duocarmycin D
Duocarmycin SA
CC-1065
Antibody-drug conjugates
The DNA modifying agents such as duocarmycin are being used in the development of
antibody-drug conjugate or ADCs. Scientists at The Netherlands-based
Byondis (formerly Synthon) have combined a unique linkers with duocarmycin derivatives that have a hydroxyl group which is crucial for
biological activity. Using this technology scientists aim to create ADCs having an optimal therapeutic window, balancing the effect of potent cell-killing agents on tumor cells versus healthy cells.[12]
Synthetic analogs
The synthetic analogs of duocarmycins include
adozelesin,
bizelesin, and
carzelesin. As members of the cyclopropylpyrroloindole family, these investigational drugs have progressed into clinical trials for the treatment of cancer.[citation needed]
Bizelesin
Bizelesin is antineoplastic antibiotic which binds to the minor groove of DNA and induces interstrand cross-linking of DNA, thereby inhibiting DNA replication and RNA synthesis. Bizelesin also enhances p53 and p21 induction and triggers G2/M cell-cycle arrest, resulting in cell senescence without apoptosis.[13]
^"Cytotoxic Agents". ADC Review/Journal of Antibody-drug Conjugates. October 29, 2013.
^Boger, Dale L. (1991). "Duocarmycins: a new class of sequence selective DNA minor groove alkylating agents". Chemtracts: Organic Chemistry. 4 (5): 329–49.
^Tercel, Moana; McManaway, Sarah P.; Leung, Euphemia; Liyanage, H. D. Sarath; Lu, Guo-Liang; Pruijn, Frederik B. (2013). "The Cytotoxicity of Duocarmycin Analogues is Mediated through Alkylation of DNA, not Aldehyde Dehydrogenase 1: A Comment". Angewandte Chemie International Edition. 52 (21): 5442–6.
doi:
10.1002/anie.201208373.
PMID23616474.
^Tietze, Lutz F.; Krewer, Birgit (2009). "Antibody-Directed Enzyme Prodrug Therapy: A Promising Approach for a Selective Treatment of Cancer Based on Prodrugs and Monoclonal Antibodies". Chemical Biology & Drug Design. 74 (3): 205–11.
doi:
10.1111/j.1747-0285.2009.00856.x.
PMID19660031.
S2CID205913105.
^Cacciari, Barbara; Romagnoli, Romeo; Baraldi, Pier Giovanni; Ros, Tatiana Da; Spalluto, Giampiero (2000). "CC-1065 and the duocarmycins: Recent developments". Expert Opinion on Therapeutic Patents. 10 (12): 1853–71.
doi:
10.1517/13543776.10.12.1853.
S2CID85939310.