Synthesis, DNA intercalation and 3D QSAR analysis of cis-2,4,5-trisubstituted-1,3-dithiolanes as a novel class of antitumor agents
| Autor: | Reen Yen Kuo, Shiqi Peng, Fei Huang, Keduo Qian, Xiaoyi Zhang, Chao Wang, Kuo Hsiung Lee, Susan L. Morris-Natschke, Ming Zhao |
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| Rok vydání: | 2009 |
| Předmět: |
Quantitative structure–activity relationship
Molecular model Stereochemistry Clinical Biochemistry Intercalation (chemistry) Molecular Conformation Quantitative Structure-Activity Relationship Pharmaceutical Science Antineoplastic Agents Biochemistry Chemical synthesis Mice chemistry.chemical_compound Heterocyclic Compounds In vivo Neoplasms Drug Discovery medicine Animals Molecular Biology Organic Chemistry Acetal DNA Intercalating Agents chemistry Cytarabine Molecular Medicine medicine.drug |
| Zdroj: | Bioorganic & Medicinal Chemistry. 17:6085-6095 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2009.06.011 |
| Popis: | Acid-catalyzed transacetalation of dimethyl (2R,3S)-2,3-dimercapto-succinate and 1,1,3,3-tetramethoxypropane provided cis-4,5-dimethoxycarbonyl-2-(2',2'-dimethoxyethyl)-1,3-dithiolane (2) in 77% yield. The esterification of 2 and l-amino acids provided 18 active antitumor cis-2-carbonylmethyl-4,5- di(l-aminoacyloxymethyl)-1,3-dithiolane analogs (5a-r). Five compounds (5b,c,e,k,p) exhibited remarkable antitumor activity in in vivo assays. The in vivo antitumor potency of 5e,k,p at 44.64micromol/kg was similar to that of cytarabine at 89.28micromol/kg. Several different assay systems, including UV-vis of CT DNA with or without the representative compound 5d and CD spectra of CT DNA with or without representative compounds 5b,f,i demonstrated that DNA is the target of 5a-r. A 3D QSAR model was established to elucidate quantitative relationships between in vivo antitumor activity and analog structures. An equation with r(2) equal to 0.992 was built to predict antitumor activity of unknown cis-2,4,5-trisubstituted-1,3-dithiolane analogs. |
| Databáze: | OpenAIRE |
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