V. L. Narayanan

Preclinical antitumor activity of batracylin (NSC 320846)

SummaryBatracylin (NSC 320846, BAY H 2049), given ip on days 2 and 9 at a dose of 400 mg/kg, inhibited tumor growth completely in 80–100% of mice with early-stage colon adenocarcinoma 38. Therapeutic efficacy against this subcutaneously implanted tumor was retained upon oral administration of Batracylin although, compared to ip treatment, larger doses were required. Batracylin also caused regression of advanced (400 mg) colon 38 tumors. Only modest activity was observed for this compound against P388 leukemia, but P388 sublines with acquired resistance to either adriamycin or cisplatin demonstrated collateral sensitivity. Batracylin currently is undergoing toxicological evaluation by NCI prior to clinical trials.

Computer Assisted Structure-Antileukemic Activity Correlations of Organotin Compounds and Initial Exploration of their Potential Anti-HIV Activity

The National Cancer Institute (NCI) and others have a continuing interest in exploring the anticancer and recently the anti-HIV potential of metal and metalloid compounds (Cleare et al 1980; Lippard 1983; Crowe et al 1980). The number of metal-containing compounds in the NCI collection is given in Table 1. Organotin compounds are the largest class among metals as represented by more than 2,000 compounds. This emphasis is the natural consequence of the wide biological use (Cardarelli 1972; Arakawa et al 1988) of tin compounds and their subsequent availability for screening by the NCI. A good deal of work has been done on the chemistry (Davis et al 1980; Wardell 1967), toxicology (Cardarelli 1986; Smith et al 1975), and metabolism (Thayer 1974; Kimmel 1977) of tin compounds. This study focuses on the structure-anticancer activity of tin-containing compounds evaluated by the NCI.

Computer-Assisted Structure-Activity Correlations

Several types of Michael acceptors, including alpha,beta-unsaturated ketones, lactones, and lactams, have been extensively studied as potential anticancer agents. A concerted effort was made to explore the relationship between the structures of these compounds and their antitumor activity against P388 and L1210 leukemias. This article describes the computer-assisted structure-activity evaluation of more than 14,000 compounds, representing different classes of Michael acceptors, in the NCI file. In this study, advantage has been taken of the computers ability to search substructures according to precise definitions and to manipulate these substructures utilizing Boolean logic. Olefinic conjugated Michael-type acceptors, e.g., styrenes with different activating groups, cinnamic acid derivatives, and alpha,beta-unsaturated nitro, cyano, sulfone, sulfoxide, and acetylenic compounds, have shown appreciable activity against P388 lymphocytic leukemia. The analysis of lactones and lactams includes substructures representing a wide variety of exocyclic and endocyclic alpha,beta-unsaturated compounds. The analysis describes the effect of certain groups, such as an --OH, --OR, alpha,beta-unsaturated ester, or epoxide, adjacent to the alpha,beta-unsaturated center, on the antitumor activity of these compounds. A combination of one or more of these activating groups with an alpha-methylene-gamma-lactone moiety significantly enhanced the activity against P388. In general, many of the classes of compounds studied have shown poor activity against the more stringent L1210 lymphoid leukemia.

Computer-assisted structure — Antileukemic activity analysis of purines and their aza and deaza analogs

The National Cancer Institute (NCI), in a continuing effort to discover novel anticancer leads, has screened more than 350,000 compounds. Thus, extensive chemical and biological database files have become available. The recent establishment of the chemistry-biology computer interlink offers the opportunity to undertake carefully planned structure-activity studies. Although a selective acquisition approach in the screening program is now adopted by the NCI [1] promising antitumor leads still have to be developed from the screening of large numbers of compounds in various tumor systems. These novel leads can then be optimized through both structure-activity analysis of the total NCI file and analog synthesis.