ABSTRACT
Analogues of the natural product noscapine were synthesized and their potential as antitumor agents evaluated. The discovery of a novel regioselective O-demethylation facilitated the synthesis of the potent aniline 6, which arrests mammalian cells in the G2/M phase of the cell cycle at 0.1 microM and also affects tubulin polymerization. Aniline 6 is orally bioavailable and is 250-fold more potent than noscapine in reducing cell proliferation in rapidly dividing cells.
Subject(s)
Antineoplastic Agents/chemical synthesis , Noscapine/analogs & derivatives , Noscapine/chemical synthesis , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Biopolymers , Cell Line , Drug Screening Assays, Antitumor , G2 Phase/drug effects , HeLa Cells , Humans , Mice , Microtubules/drug effects , Noscapine/pharmacokinetics , Noscapine/pharmacology , Stereoisomerism , Tubulin/chemistry , Tubulin Modulators/chemical synthesis , Tubulin Modulators/chemistryABSTRACT
Analogues of the natural product noscapine were synthesized, and their potential as antitumor agents were examined. The discovery of a novel regio- and stereoselective O-demethylation led to the synthesis of several O-alkylated analogues that induced an unexpected S-phase arrest of mammalian cells. Compound 4a was the most potent analogue inhibiting cell proliferation at an EC(50) of 1.9 microM.
Subject(s)
Antineoplastic Agents/chemical synthesis , Noscapine/analogs & derivatives , Noscapine/chemical synthesis , S Phase/drug effects , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , Noscapine/chemistry , Noscapine/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Flap endonuclease-1 (FEN1) is a key enzyme involved in base excision repair (BER), a primary pathway utilized by mammalian cells to repair DNA damage. Sensitization to DNA damaging agents is a potential method for the improvement of the therapeutic window of traditional chemotherapeutics. In this paper, we describe the identification and SAR of a series of low nanomolar FEN1 inhibitors. Over 1000-fold specificity was achieved against a related endonuclease, xeroderma pigmentosum G (XPG). Two compounds from this series significantly potentiate the action of methyl methanesulfonate (MMS) and temozolamide in a bladder cancer cell line (T24). To our knowledge, these are the most potent endonuclease inhibitors reported to date.
Subject(s)
Dacarbazine/analogs & derivatives , Enzyme Inhibitors/chemistry , Flap Endonucleases/antagonists & inhibitors , Urea/analogs & derivatives , Cell Line, Tumor , DNA Damage , Dacarbazine/chemistry , Enzyme Inhibitors/pharmacology , Humans , Methyl Methanesulfonate/chemistry , Structure-Activity Relationship , Temozolomide , Urea/pharmacology , Urinary Bladder Neoplasms , Xeroderma PigmentosumABSTRACT
There have been several recent reports of chemopotentiation via inhibition of DNA repair processes. Flap endonuclease 1 (FEN1) is a key enzyme involved in base excision repair (BER), a primary pathway utilized by mammalian cells to repair DNA damage. In this report, we describe the identification and SAR of a series of 2,4-diketobutyric acid FEN1 inhibitors.
