title: Multicomponent assembly of 4-aza-podophyllotoxins: A fast entry to highly selective and potent anti-leukemic agents.
abstract: The aim of this study was the synthesis and lead structure selection of a best anti-leukemic agent from a library of aza-podophyllotoxin analogues (APTs). To this end, we report a scalable, modified multicomponent reaction using a "sacrificial" aniline partner as a more general route to rapidly construct the pivotal library of 50 APT analogues. Our preliminary structure activity relationship studies for anti-leukemic activity also address the innate toxicity of these compounds against non-malignant cells. As a result, we identified 2 novel compounds 2ca' and 2jc' more potent than etoposide 1 (25-60 fold) having high selectivity against the human THP-1 leukemia cell line and a minimal toxicity (IC50 of 9.3 ± 0.8 and 19.6 ± 1.4 nM respectively) which represent the best candidates for further pharmacological optimization.
authors.affiliation: Department of Chemistry and Biochemistry, Florida Atlantic University, Boca Raton, FL 33431, United States.
authors.forename: Nagalakshmi
authors.initials: N
authors.lastname: Jeedimalla
authors.affiliation: Department of Chemistry and Biochemistry, Florida Atlantic University, Boca Raton, FL 33431, United States.
authors.forename: Madison
authors.initials: M
authors.lastname: Flint
authors.affiliation: Torrey Pines Institute for Molecular Studies, Port St. Lucie, FL 34987, United States.
authors.forename: Lyndsay
authors.initials: L
authors.lastname: Smith
authors.affiliation: Department of Chemistry and Biochemistry, Florida Atlantic University, Boca Raton, FL 33431, United States.
authors.forename: Alberto
authors.initials: A
authors.lastname: Haces
authors.affiliation: Torrey Pines Institute for Molecular Studies, Port St. Lucie, FL 34987, United States. Electronic address: dzm0032@auburn.edu.
authors.forename: Dmitriy
authors.initials: D
authors.lastname: Minond
authors.affiliation: Department of Chemistry and Biochemistry, Florida Atlantic University, Boca Raton, FL 33431, United States. Electronic address: sroche2@fau.edu.
authors.forename: Stéphane P
authors.initials: SP
authors.lastname: Roche
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D057809:HEK293 Cells; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology*; D015394:Molecular Structure; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014343:Trypan Blue / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D014343:Trypan Blue; D011034:Podophyllotoxin
keywords: AML; Anti-leukemic agents; Aza-podophyllotoxins; Etoposide; Multicomponent reactions; SAR study