1. Synthesis and antitumor activity of duocarmycin derivatives: A-ring pyrrole compounds bearing beta-(5',6',7'-trimethoxy-2'-indolyl)acryloyl group
A Okamoto, S Nagamura, M Okabe, N Amishiro, E Kobayashi, H Saito, K Gomi Bioorg Med Chem . 2000 Jul;8(7):1637-43. doi: 10.1016/s0968-0896(00)00086-9.
A series of A-ring pyrrole derivatives of duocarmycin bearing beta-(5',6',7'-trimethoxy-2'-indolyl)acryloyl group were synthesized, and evaluated for in vitro anticellular activity against HeLa S3 cells and in vivo antitumor activity against murine sarcoma 180 in mice. New Seg-B analogues bearing beta-(5',6',7'-trimethoxy-2'-indolyl)acryloyl group containing double bond as spacer had lower peripheral blood toxicity than the derivatives bearing 5',6',7'-trimethoxyindole-2'-carboxyl group in Seg-B of the natural type. Moreover, most of them exhibited potent antitumor activity against in vivo murine tumor models.
2. Synthesis and antitumor activity of water-soluble duocarmycin B1 prodrugs
A Asai, S Nagamura, E Kobayashi, H Saito, K Gomi Bioorg Med Chem Lett . 1999 Oct 18;9(20):2995-8. doi: 10.1016/s0960-894x(99)00518-1.
The water-soluble duocarmycin B1 prodrugs such as glycoside 3, phosphate 4 and carbamate 5 were synthesized for improving biological and pharmaceutical profiles of duocarmycin. Among these prodrugs, N-methylpiperazinylcarbamoyl derivative 5 exhibited potent antitumor activity against several human tumors in vivo.
3. Interconversion and stability of duocarmycins, a new family of antitumor antibiotics: correlation to their cytotoxic and antimicrobial activities in vitro
A Mihara, H Nakano, T Ogawa, I Takahashi, K Takahashi, M Ichimura Oncol Res . 1993;5(4-5):165-71.
Stability and interconversion of duocarmycins were studied in relation to their cytotoxicities and antimicrobial activities. The compounds studied included duocarmycin A and SA, which have a spirocyclopropylhexadienone moiety, and four halogenated seco-compounds of duocarmycin A: duocarmycin B1, B2, C1 and C2, from which the cyclopropane ring structure is absent. Duocarmycins were potent cytotoxic compounds to cells. The cytotoxic activity seen on Balb 3T3/H-ras cells after 72 h drug exposure was in the following order (IC50 (nM): concentration for 50% growth inhibition); SA (0.05) > A (0.3) > B2 (1.5) > B1 (3.0) > C2 (20) > C1 (40). Average minimum inhibitory concentrations (MICs) of duocarmycins against microorganisms showed essentially the same ranking order as that of cytotoxicity. There was a large difference between SA and A in their stability in aqueous solvents. For halogenated seco-compounds, a good correlation was found between their cytotoxicities in vitro and their conversion rate to duocarmycin A, suggesting that halogenated seco-compounds undergo closure to the spirocyclopropylhexadienone structure, the pertinent active form, in cells.
