ABSTRACT
A series of novel 3-[4-phenyl-1-piperazinyl]-1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-1-trans-propenes and related compounds were synthesized and evaluated by their cytotoxic activity against several tumor cell lines in vitro and in vivo antitumor activity against some tumor models when administered both intraperitoneally and orally. Compounds with the 3-chloropyridin-2-yl group (9g) and the 3-fluoro-5-substituted phenylpiperazinyl group (29b, c, and e) showed significantly potent cytotoxicity by in vitro testing. Among them, the 3-cyano-5-fluorophenyl derivative (29b) exhibited potent antitumor activity against several tumor cells including human carcinoma without causing undesirable effects in mice.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Piperazines/chemical synthesis , Piperazines/pharmacology , Propane/analogs & derivatives , Propane/chemical synthesis , Propane/pharmacology , Animals , Cell Line, Tumor , Chemical Phenomena , Chemistry, Physical , Drug Screening Assays, Antitumor , Humans , Magnetic Resonance Spectroscopy , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplasm Transplantation , Structure-Activity RelationshipABSTRACT
An investigation into the structure-activity relationship of a lead compound, prolyl-5-aminopentanoic acid 4, led to the identification of a novel series of 4-piperidinylacetic acid, 1-piperazinylacetic acid, and 4-aminobenzoic acid derivatives as potent VLA-4 antagonists with low nanomolar IC(50) values. A representative compound morpholinyl-4-piperidinylacetic acid derivative (13d: IC(50)=4.4 nM) showed efficacy in the Ascaris-antigen sensitized murine airway inflammation model by oral administration.
Subject(s)
Integrin alpha4beta1/antagonists & inhibitors , Morpholines/pharmacology , Piperidines/pharmacology , Administration, Oral , Animals , Asthma/etiology , Asthma/metabolism , Mice , Morpholines/administration & dosage , Morpholines/chemistry , Piperidines/administration & dosage , Piperidines/chemistryABSTRACT
Pyrimidinyl pyrazole derivatives 1-4, prepared as a new scaffold of an anti-tumor agent, showed antiproliferative activity against human lung cancer cell lines and inhibited tubulin polymerization. Furthermore, it was found that compound 2 bound at the colchicine site on tubulin, but the tubulin binding pattern was different from that of colchicine. Here, we describe the synthesis of the derivatives and the differences of the action mechanism on tubulin polymerization inhibition between compound 2 and colchicine.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Binding, Competitive/drug effects , Colchicine/pharmacology , Drug Screening Assays, Antitumor , Humans , Indicators and Reagents , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Microtubules/drug effects , Protein Binding/drug effects , Tubulin/drug effects , Tubulin Modulators , Tumor Cells, CulturedABSTRACT
A series of novel 3-substituted-1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-1-trans-propenes in order to improve the in vitro and in vivo activity of our prototype 3-[4-(3-chlorophenyl)-1-piperazinyl]-1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-1-trans-propene (2) were synthesized and evaluated by assays of growth inhibition against several tumor cell lines in vitro and antitumor activity against some tumor models when dosed both intraperitoneally and orally in vivo. Compounds 7a and 7e, the 3,5-difluorophenyl and 3,5-dichlorophenyl analogues of 2, respectively, showed significantly more potent cytotoxicity than 2 in vitro and potent antitumor activities without causing decrease of body temperature related to side effects.
