title: Discovery and investigation of antiproliferative and apoptosis-inducing properties of new heterocyclic podophyllotoxin analogues accessible by a one-step multicomponent synthesis.
abstract: Podophyllotoxin has been extensively used as a lead agent in the development of new anticancer drugs. On the basis of the previously reported simplified 4-aza-2,3-didehydro podophyllotoxin analogues, we implemented a bioisosteric replacement of the methylenedioxybenzene subunit with a pyrazole moiety to afford tetracyclic dihydropyridopyrazoles. Libraries of these structurally simple analogues are prepared by a straightforward one-step multicomponent synthesis and demonstrated to display antiproliferative properties in a number of human cancer cell lines. These new heterocycles potently induce apoptosis in cancerous Jurkat cells even after a short 24 h exposure. In contrast, no apoptosis is detected in primary lymphocytes under the same treatment conditions. The ease of synthesis and encouraging biological activities make the presented library of dihydropyridopyrazoles promising new leads in anticancer drug design.
authors: Department of Organic Chemistry, Timiryazev Agriculture Academy, Moscow 127550, Russia. intelbioscan@mtu-net.ru
authors: Igor V
authors: IV
authors: Magedov
authors: Madhuri
authors: M
authors: Manpadi
authors: Severine Van
authors: SV
authors: Slambrouck
authors: Wim F A
authors: WF
authors: Steelant
authors: Elena
authors: E
authors: Rozhkova
authors: Nikolai M
authors: NM
authors: Przheval'skii
authors: Snezna
authors: S
authors: Rogelj
authors: Alexander
authors: A
authors: Kornienko
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D006575:Heterocyclic Compounds, 3-Ring; D011720:Pyrazoles; D053148:Caspase 3; D011034:Podophyllotoxin