An integrated molecular modeling system for designing and studying organic and bioorganic molecules and their molecular complexes using molecular mechanics is described. The graphically controlled, atom‐based system allows the construction, display and manipulation of molecules and complexes having as many as 10,000 atoms and provides interactive, state‐of‐the‐art molecular mechanics on any subset of up to 1,000 atoms. The system semiautomates the graphical construction and analysis of complex structures ranging from polycyclic organic molecules to biopolymers to mixed molecular complexes. We have placed emphasis on providing effective searches of conformational space by a number of different methods and on highly optimized molecular mechanics energy calculations using widely used force fields which are supplied as external files. Little experience is required to operate the system effectively and even novices can use it to carry out sophisticated modeling operations. The software has been designed to run on Digital Equipment Corporation VAX computers interfaced to a variety of graphics devices ranging from inexpensive monochrome terminals to the sophisticated graphics displays of the Evans & Sutherland PS300 series.

This study summarizes the antitumor properties of a number of sulofenur thiophene analogs against subcutaneously implanted 6C3HED lymphosarcoma with structural modification of the aryl moiety of the sulfonamide portion of the diarylsulfonylureas. The spectrum of activity of N-(p-chlorophenyl)-N'- [(5-methoxy-2-thienyl)sulfonyl]urea in the HXGC3, VRC5, CX-1, and LX-1 cell lines is also presented.

In addition to the Corey,la Woodward,16 and Storklc ringdisconnection methods used for the formation of poly-

A practical, total synthesis of seco-(+)-oxaduocarmycin 3a, an analogue of the highly cytotoxic natural product, duocarmycin SA (1), is described. The 13-step synthesis features a novel and efficient intramolecular aryl radical cyclization onto a vinyl chloride as a direct entry to the (chloromethyl)indoline alkylating subunit 14. Subsequent resolution, utilizing a preparative Chiralpak AD column, provided enantiomerically pure alkylating subunits 14a and 14b which were elaborated to seco-(+) and ent-(-)-oxaduocarmycins, 3a and 3b, respectively. The natural enantiomer 3a was active at pM concentrations and exhibited 7-50-fold higher potentcy than its enantiomer 3b in in vitro cytotoxicity assays.

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.