Antitumor agents. 1771. Design, syntheses, and biological evaluation of novel etoposide analogs bearing pyrrolecarboxamidino group as DNA topoisomerase II inhibitors

DNA minor groove binders as potential antitumor and antimicrobial agents

“…The hybrid 190a, characterized by the presence of one pyrrole ring, displayed topoisomerase II inhibitory activity superior to etoposide. 219 Another important example of conjugate with moieties related to important antitumor drugs was illustrate by the conjugates between the distamycin frame and its imidazole analog, and the topoisomerase I inhibitor 10-hydroxy camptothecin. These derivatives, where the compounds 191a and 191b represent the most potent derivatives of the series against KB cells, are characterized by a significant topoisomerase I inhibitory activity but, at the same time, these are one-two orders of magnitude less cytotoxic than camptothecin.…”

Novel antitumor agents from higher plants

“…We first chose a structural component of the cytotoxic polypeptide netropsin, and linked this minor groove binding functional groups to a p-aminoanilino epipodophyllotoxin through an amide bond. 43 Compound 23 with a 1-methyl-4-nitro-2-pyrrolecarboxyl group was extremely active (17), 24 and 25 were more cytotoxic in several cancer cell lines including HOP-62 leukemia, SW-620 colon cancer, MCF/ADR adriamycin-resistant breast cancer, and A-498 renal cancer (Table IV). More importantly, in KB and drug-resistant KB-variants, 24 and 25 showed a lower-fold decrease in cytotoxicity (ca.…”

“…[54][55][56] Bruceoside C (41) shows excellent activity (ED 50 Ͻ 0.1 g/mL) in KB and RPMI-7951 cell lines, and brusatol (42) is also quite active. A related compound bruceantin (43) 57 from Brucea antidysenterica (Simaroubaceae) has been tested in phase II clinical trials, but has not progressed to drug development. Like the helenalin esters above, the bisbrusatolyl and bisbruceantinyl malonates are also active.…”

Anticancer Drug Design Based on Plant-Derived Natural Products¹

“…Thus, if the minor groove binding ability of our 4-amino-epipodophyllotoxin analogs is increased, the topo II inhibition should also increase. We linked p-aminoanilino epipodophyllotoxin to two known minor groove binding functional groups (structural components of the cytotoxic polypeptide netropsin) through an amide bond [30]. The new compound (21) with a 1-methyl-4-nitro-2-pyrrolecarboxyl group was extremely potent against MOLT-4 leukemia and MCF-7 breast cancer cell lines; its log GI 50 values were less than -8, while those of etoposide (12) Based upon our CoMFA studies mentioned above, we designed and synthesized several new 4-ß-substituted 4)-O-demethyl-4-desoxypodophyllotoxins bearing mono-, di-, and tri-substituted anilines [68].…”

“…(1) The three methoxy groups in the A ring are essential for maintaining full tubulin binding affinity and ITP; all mono (e.g., 27)-, di (e.g., 28)-, and tri-demethylated (29,30) derivatives were less active than the fully A-ringmethylated parent compounds (25,26) [24]. Of the three possible mono-demethylthiocolchicines, 1-demethylthiocolchicine (27) was the least active.…”