Search

We report herein the synthesis and biological evaluation of two series of 7-substituted norfloxacin derivatives. Most compounds tested in this study demonstrated better activity against methicillin-resistant Staphylococcus aureus than norfloxacin. Preliminary in vitro evaluation indicated that the 7-[4-(2-hydroxyiminoethyl)piperazin-1-yl] derivatives 3b-e possess distinct cytotoxicity profiles as compared with their alpha-methylene-gamma-butyrolactone counterparts, 4b,e: i.e., excellent activities against the renal cancer subpanel. Among them, 1-ethyl-6-fluoro-7-¿4-[2-(4-chlorophenyl)-2-hydroxyiminoethyl]-1-p ipe razinyl¿-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (3d) demonstrated the most significant activities against renal cancer cell lines, with log GI(50) values of -6.40 against CAK-1, -6.14 against RXF 393, and -7.54 against UO-31, compared with a mean log GI(50) value of -5.03.

Purpose: The main objective of this investigation was to explore the cytotoxic structure-activity relationships of gamma-substituted gamma-aryloxymethyl-alpha-methylene-gamma-butyrolactones against cancer cells., Methods: The target compounds were synthesized in two steps commencing with aryl-OH which was treated with a bromomethyl ketone followed by the Reformatsky-type condensation., Results: Seven types of alpha-methylene-gamma-butyrolactones were evaluated in vitro against 60 human cancer cell lines derived from nine cancer cell types. The average values of log GI50 indicated that for the aryl portion, potencies of these alpha-methylene-gamma-butyrolactones are in a decreasing order of quinolin-2(1H)-one (or 2-hydroxyquinoline, 21, -5.89) > quinoline (19, -5.79) > 2-methylquinoline (20, -5.69) >8-hydroxyquinoline (17,-5.64) > 2-naphthalene (16, -5.59) > benzene (15, -4.90). The same order was obtained for both log TGI and log LC50. However, for the gamma-substituent, the potencies are in a decreasing order of biphenyl (16f-21f) > phenyl and 4-substituted phenyl (16b-e-21b-e) > methyl (16a-21a)., Conclusions: Unlike cardiovascular activities of alpha-methylene-gamma-butyrolactones in which a gamma-methyl substituent is necessary for vasorelaxing effect while a phenyl or a halogen-substituted phenyl is prefer for the antiplatelet activities, a gamma-biphenyl substituent proved to be the best for their cytotoxicities against various cancer cell lines tested.

Certain alpha-methylene-gamma-(4-substituted phenyl)-gamma-butyrolactone bearing thymine, uracil, and 5-bromouracil were synthesized and evaluated for their anticancer activity. These compounds demonstrated a strong growth inhibitory activity against leukemia cell lines. The anticancer potency for the substituents of the lactone C(gamma)-phenyl is in an order of 4-Ph > 4-Cl, 4-Br > 4-Me, 4-NO2 > 4-F. For the pyrimidine portion, 5-bromouracil is more potent than uracil and thymine.

Certain gamma-aryloxymethyl-alpha-methylene-gamma-phenyl- gamma-butyrolactones were synthesized and evaluated for their anticancer activity. These compounds demonstrated a strong growth inhibitory activity against leukemia cell lines but are relatively inactive against non-small cell lung cancers and CNS cancers. The anticancer potency for aryl portion is in an order of quinoline > 8-hydroxyquinoline > 2-methylquinoline >> naphthalene >> benzene.

A total of ten pyrimidine alpha-methylene-gamma-butyrolactones were synthesized as potential antitumor agents on the basis of their possible action as Michael acceptors for DNA/RNA and cellular enzymes. The synthesis of these heterocycles involved a convenient Reformatsky-type reaction of pyrimidinyl ketones with ethyl alpha-(bromomethyl)acrylate. The preliminary in vitro cytotoxic assay indicated that these synthetic compounds were essentially active against the growth of KB, Hep-2, HeLa and Colo-205 cells. Among them, 5'-biphenyl-5'-(uracil-1-ylmethyl)-2'-oxo-3'-methylenetetrahydr ofuran (5f) demonstrated to be the most potent antileukemic agent.