Synthesis, DNA intercalation and 3D QSAR analysis of cis-2,4,5-trisubstituted-1,3-dithiolanes as a novel class of antitumor agents.
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.
Huang
Fei
F
Peking University, Beijing, PR China.
Zhao
Ming
M
Zhang
Xiaoyi
X
Wang
Chao
C
Qian
Keduo
K
Kuo
Reen-Yen
RY
Morris-Natschke
Susan
S
Lee
Kuo-Hsiung
KH
Peng
Shiqi
S
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000737:chemistry*; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D007364:Intercalating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008968:Molecular Conformation; D009369:Neoplasms / Q000188:drug therapy; D021281:Quantitative Structure-Activity Relationship
D000970:Antineoplastic Agents; D006571:Heterocyclic Compounds; D007364:Intercalating Agents; C012948:1,3-dithiolane; D004247:DNA