Structural simplification of bioactive natural products with multicomponent synthesis: dihydropyridopyrazole analogues of podophyllotoxin.

A three-component condensation of 5-amino-3-methylpyrazole, tetronic acid, and various aromatic, heteroaromatic, and aliphatic aldehydes leads to the formation of dihydropyridopyrazole analogues of a cytotoxic lignan podophyllotoxin. This new heterocyclic scaffold-based library allows a drastic reduction of the structural complexity of the natural product with the retention of its potent cytotoxic properties. Similarly to podophyllotoxin, the presented analogues induce apoptosis in Jurkat cells.

[1]  Nonenolizable podophyllotoxin derivatives. , 1977, Journal of medicinal chemistry.

[2]  Junyong Zhang,et al.  A multi-component reaction for the synthesis of N-substituted furo[3,4-b]quinoline derivatives under microwave irradiation , 2006 .

[3]  Youngjae You.  Podophyllotoxin derivatives: current synthetic approaches for new anticancer agents. , 2005, Current pharmaceutical design.

[4]  L. Verotta,et al.  Synthesis and cytotoxic evaluation of combretafurans, potential scaffolds for dual-action antitumoral agents. , 2006, Journal of medicinal chemistry.

[5]  L. Bohlin,et al.  Podophyllotoxin derivatives : drug discovery and development , 1996 .

[6]  S. Nilsson,et al.  Estrogen receptor beta-subtype selective tetrahydrofluorenones: use of a fused pyrazole as a phenol bioisostere. , 2006, Bioorganic & medicinal chemistry letters.

[7]  M. Gordaliza,et al.  Antitumor properties of podophyllotoxin and related compounds. , 2000, Current pharmaceutical design.

[8]  B. Insuasty,et al.  Synthesis of 4‐aryl‐4,7,8,9‐tetrahydro‐6H‐pyrazolo[3,4‐b]quinolin‐5‐ones , 1998 .

[9]  T. Imbert.  Discovery of podophyllotoxins. , 1998, Biochimie.

[10]  J. Sullivan,et al.  Structure-Activity studies for a novel series of tricyclic dihydropyrimidines as K(ATP) channel openers (KCOs). , 2002, Bioorganic & medicinal chemistry letters.

[11]  H. Itokawa,et al.  4-Aza-2,3-dehydro-4-deoxypodophyllotoxins: simple aza-podophyllotoxin analogues possessing potent cytotoxicity. , 2000, Bioorganic & medicinal chemistry letters.

[12]  H. Itokawa,et al.  A facile synthesis of the 4-aza-analogs of 1-arylnaphthalene lignans chinensin, justicidin B, and Taiwanin C , 1997 .

[13]  T. Mosmann.  Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. , 1983, Journal of immunological methods.

[14]  J. Loike,et al.  Lignans: Chemical, Biological and Clinical Properties , 1990 .

[15]  J. N. Low,et al.  Regioselective synthesis of 4,7,8,9-tetrahydro-2 H -pyrazolo[3,4- b ]quinolin-5(6 H )-ones. Mechanism and structural analysis , 2001 .