Duocarmycin

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 Synthon (formerly Syntarga) have combined a unique linkers with duocarmycin derivatives that have a hydroxyl group which is crucial for biological activity. Using this technology scientists aims 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.

Bizelesin

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]

Adozelesin

Carzelesin

References

1. Yasuzawa, Tohru; Iida, Takao; Muroi, Ken'Ichi; Ichimura, Michio; Takahashi, Keiichi; Sano, Hiroshi (1988). "Structures of Duocarmycins, novel antitumor antibiotics produced by Streptomyces sp". Chemical & Pharmaceutical Bulletin. 36 (9): 3728–31. doi:10.1248/cpb.36.3728.
2. Takahashi, Isami; Takahashi, KEI-Ichi; Ichimura, Michio; Morimoto, Makoto; Asano, Kozo; Kawamoto, Isao; Tomita, Fusao; Nakano, Hirofumi (1988). "Duocarmycin A, a new antitumor antibiotic from Streptomyces". The Journal of Antibiotics. 41 (12): 1915–7. doi:10.7164/antibiotics.41.1915. PMID 3209484.
3. "Cytotoxic Agents". ADC Review/Journal of Antibody-drug Conjugates. October 29, 2013.
4. Boger, Dale L. (1991). "Duocarmycins: a new class of sequence selective DNA minor groove alkylating agents". Chemtracts: Organic Chemistry. 4 (5): 329–49.
5. 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. PMID 23616474.
6. Boger, D. L. (1993). "Design, synthesis, and evaluation of DNA minor groove binding agents". Pure and Applied Chemistry. 65 (6): 1123–32. doi:10.1351/pac199365061123.
7. Boger, Dale L.; Johnson, Douglas S. (1995). "CC-1065 and the Duocarmycins: Unraveling the Keys to a New Class of Naturally Derived DNA Alkylating Agents". Proceedings of the National Academy of Sciences of the United States of America. 92 (9): 3642–9. Bibcode:1995PNAS...92.3642B. doi:10.1073/pnas.92.9.3642. PMC 42018. PMID 7731958.
8. 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.
9. 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.
10. Liu, C; Tadayoni, B M; Bourret, L A; Mattocks, K M; Derr, S M; Widdison, W C; Kedersha, N L; Ariniello, P D; Goldmacher, V S (1996-08-06). "Eradication of large colon tumor xenografts by targeted delivery of maytansinoids". Proceedings of the National Academy of Sciences of the United States of America. 93 (16): 8618–8623. Bibcode:1996PNAS...93.8618L. doi:10.1073/pnas.93.16.8618. ISSN 0027-8424. PMC 38722. PMID 8710920.
11. "Duocarmycin analogues". ADC Review/Journal of Antibody-drug Conjugates. November 26, 2014. Archived from the original on November 26, 2014.
12. Hofland, Peter. "First-in-Human Trial With SYD985 Evaluates Safety and Efficacy in Cancer Patients". ADCReview /Journal of Antibody-drug Conjugates (November 2014).
13. "Bizelesin". MedKoo Biosciences.