Total synthesis and biological properties of novel antineoplastic (chloromethyl)furanoindolines: an asymmetric hydroboration mediated synthesis of the alkylation subunits

Abstract

1,2-Dihydro-1-(chloromethyl)-5-hydroxy-8-methyl-3H-furano[3,2-e]in dole (CFI) as a novel replacement of the cyclopropylpyrroloindoline (CPI) alkylation subunit of CC-1065, U-71184, and U-73975 (adozelesin) has been synthesized and incorporated into a series of efficacious antineoplastic agents. A partial solution to an asymmetric synthesis of the CFI alkylation subunit has been achieved by the implementation of an asymmetric hydroboration reaction of an intermediate 3-methyleneindoline (13). Extension to the asymmetric synthesis of the CBI and CI alkylation subunits is presented. The demonstration and comparative study of the sequence-selective DNA alkylation properties of the CFI-based agents are detailed, and the preliminary in vitro and in vivo antineoplastic properties of these agents in the human epidermoid cell lung carcinoma (T222) are described.

DNA minor groove binders as potential antitumor and antimicrobial agents

“…Each of these compounds showed different degrees of cytotoxicity and they have been used to obtain new pharmacological tools but, most importantly, they can represent possible probes for investigating the bioorganic properties of this exceptionally potent class of derivatives. [87][88][89][90][91][92][93][94][95][96][97][98][99] For the pyrazole analogs (60)(61) of N-Boc-CPI, dimer and trimer agents corresponding to the spiroderivatives 62-66 have been prepared. 98,99 Compounds 62-66 showed cytotoxicity values in a pM range against L1210 leukemia cell line and also a good cytotoxicity against multidrug resistant L1210/Dx subline.…”

“…87 The authors focused their attention on furan ring to minimize the overlap between fermentation process and chemical synthesis of CPI subunit. The cytotoxicity of synthesized compounds 67a-i has been determined against human lung epidermoid carcinoma (T222).…”

“…The most cytotoxic compound 67a, when dosed at 50-200 mg/kg intravenously on days 3, 5, and 7 in the tail vein, inhibited the growth of tumors in mice bearing a T222 burden (injected subcutaneously at day 0). 87 The only comparative results of 67a with CC-1065, regards the relative alkylation efficiency of duplex DNA, which is reported to be almost the same or slightly less effective (1.0-0.2 vs. 1).…”

CC-1065 and the duocarmycins: unraveling the keys to a new class of naturally derived DNA alkylating agents.

“…Moreover, the observations are inconsistent with alternative models based on the premise that the natural enantiomer alkylation subunit controls the alkylation selectivity. Similarly, the unnatural enantiomer of the reversed agent ent-(-)-CDPI2-DSA (26) was found to alkylate the same sites as (+)-DSA-CDPI2 (25) [77][78][79], and the extensive number of investigations directed at the subunits of the natural products (33), studies that have provided analogs (80,81) and agents containing deepseated structural modifications have proven unusually valuable in defining the relationships between structure, functional reactivity, and biological properties (82)(83)(84)(85)(86)(87)(88)(89)(90)(91)(92)(93)(94)(95)(96)(97). The acid-catalyzed activation of the DNA alkylation reaction led to the intuitive proposal that there may exist a direct relationship between the reactivity and cytotoxic activity of the agents and established the expectation that the biological potency may be enhanced as the electrophilic reactivity is increased (81).…”

Selective binding to human genomic sequences of two synthetic analogues structurally related to U-71184 and adozelesin

“…The interest around these analogues, from the pharmacologic point of view, is that these compounds could retain efficacy against a broad spectrum of mouse tumor models, including human tumor xenografts [Warpehoski et al, 1992;Aristoff, 1993;Mohamadi et al, 1994] without any evidence of delayed or irreversible toxicity at therapeutic doses [Aristoff, 1993]. Interestingly, one of the newly synthesized compounds is more active than the reference compound adozelesin in inhibiting tumor cell growth when administered to experimental animals in vivo against L1210 cells [Cozzi et al, 1996;Baraldi et al, 1997b].…”