MM3(96) PARAMETERIZATION FOR CAMPTOTHECIN ANALOGS - AN AB-INITIO AND MOLECULAR MECHANICS STUDY

Torsional parameters for MM3(96) were derived for the missing atom typ es present in the natural product camptothecin (CPT). Potential energy curves were calculated via ab initio calculations on representative c ompounds for dihedral angles containing these missing parameters. Gaus sian 92 at the restricted Hartree-Fock level of theory using the stand ard 6-31G* and 4-31G** basis sets, was used for all the quantum-mecha nics calculations. Missing MM3 torsional terms were obtained by optimi zing the V-1, V-2 and V-3 parameters such that MM3 could reproduce the ab initio torsional profile. MM3 calculated molecular structures that compare well with the ab initio results. Using the newly developed pa rameters, conformational analyses and QSAR studies of camptothecin ana logs were undertaken. MM3 predicts two distinct 'boatlike' conformatio ns for the alpha-hydroxy lactone moiety. The low-energy lactone confor mation predicted by MM3 is in general agreement with reported X-ray cr ystal structures of CPT iodoacetate and 7-ethyl-10-(4-piperidino)piper idinylcarbonyloxy CPT HCl as well as the ab initio structure of a CPT- like alpha-hydroxy lactone.