Our previously studies demonstrated that bis(hydroxymethyl)cyclopenta[a]indenes, which bear a bis(hydroxymethyl)pyrrolidine pharmacophore, exhibited potent antitumor activity in inhibiting various human tumor xenografts. We also demonstrated that these agents showed strong synergistic therapeutic efficacy in combination with arsenic trioxide (ATO) against acquire or inherited MDR human tumors in xenograft model (human lung H460 or bladder cancer resistant to cisplatin NTUB1/P). Based on these findings, we have recently synthesized a series of 1,2-bis(hydroxymethyl)indolizino[6,7-b]indols and their bis(alkylcarbomate) derivatives for antitumor evaluation. These new agents were easily prepared starting from L-tryptophane in 5 steps. The in vitro cytotoxicity studies showed that the newly synthesized derivatives possessed a broad spectrum of anticancer activity against human lymphoblastic leukemia and various solid tumor cell growth in vitro. Of these analogues, 1,2-bis(hydroxymethyl)-3,6-dimethylindolizino[6,7-b]indole (BO-1922) was selected for further antitumor studies. We found that this agent displayed potent therapeutic efficacy against human colon cancer HT-29, lung adenocarcinoma lung A549, and primary pancreatic adenocarcinoma BX-PC3 xenografts. The antitumor activity of BO-1922 was compared with Irinotecan (CPT-11) in animal xenograft model. It revealed that BO-1922 is more potent than CPT-11 against human colon cancer HT-29 xenograft; complete tumor suppression on day 20 after mice treated with BO-1922 (25 mg/kg, QD×4, intravenous injection), while, tumor relapsed on day 9 after mice treated with CPT-11 (60 mg/kg, Q2D×3, iv. inj.). Under the same drug administration conditions (dosage and schedule), BO-1922 is as potent as CPT-11 against lung cancer A549 and pancreatic cancer BX-PC3 xenografts. Although the bodyweight of all drug treated mice recovered after ceasing of treatment, it was found that BO-1922 is less toxic to the host based on the average body-weight loss. The alkaline agarose gel shifting assay showed that this agent is able to induce DNA double strand cross-linking. Flow cytomeric assay revealed that BO-1922 induced cell cycle arrest at G1/S phase in non-small cell lung carcinomas H1299. These results suggest that BO-1922 is a promising candidate for clinical application and is currently undergoing preclinical studies.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1765. doi:1538-7445.AM2012-1765