Our 17-year investigation of the potent antineoplastic constituents of this sea hare culminated in the isolation and total synthesis of the powerful dolastatin 10 (1). In order to probe the chiral and other structural parameters for such remarkable antineoplastic activity, we have first explored the synthesis and biological effects of 18 (of 128 possible) chiral isomers of dolastatin 10 when one to five asymmetric carbons in the Dil-Dap sequence were reversed. We now report that isodolastatins 3-19 (Table I) are less cytostatic than the parent pentapeptide (1, P388 ED50 pg/mL) against cell growth of the P388 lymphocytic leukemia (PS system) with ED50 values near the pg/mL level and that (19aR)-isodolastatin 10 (2) was consistently found to be up to 10-fold more cell growth inhibitory, affording an EDso of 4.9 x pg/mL. Eighteen analogues of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were synthesized and evaluated as substrates of monoamine oxidase. In general, the flexible analogues, characterized by the presence of a methylene (or ethylene) bridge between the aryl/heteroaryl and tetrahydropyridyl moieties, were better substrates of the enzyme than the conformationally restricted MPTP. It is suggested that the increased oxidative activity of these flexible analogues reflects enhanced binding due to the ability of the C-4-aryl/heteroaryl substituent to gain access to a hydrophobic pocket within the substrate binding site.