While structure-activity relationships for
vinblastine (VLB),
vincristine, deacetyl-VLB, and deacetyl-VLB
amide (
vindesine, VDS) in several
tumor and
leukemia models have been reported previously, the present study explores these relationships for a series of N-substituted
vindesine analogues. These compounds were prepared from the reaction of deacetyl-VLB
acid azide with the appropriate
amines and were characterized by mass spectral analysis, 1H and 13C NMR spectra, electrometric titration, and infrared spectra. N-Alkylvindesines have reduced activity compared to that of VDS against the Gardner
lymphosarcoma (GLS). N-beta-Hydroxyethyl-VDS surpasses
vindesine in its activity against the Ridgway
osteogenic sarcoma and the GLS, whereas against the
B16 melanoma it is less active than VDS. N-beta-(4-Hydroxyphenethyl)-VDS, envisaged as a substrate for the
enzyme tryosinase, was shown to be more active than VDS against the
B16 melanoma but has only marginal activity against the GLS. In terms of collective antitumor activity against the model systems used,
vindesine emerges as the congener with optimum qualities. Bis(N-ethylidenevindesine)
disulfide, the first example of a bridged bisvindesine and comparable to VDS in its antitumor profile, shows evidence of activity against a P388/VCR
leukemia strain known to be resistant to
maytansine as well as to
vincristine.