Novel structural motifs consisting of chiral thiazolines: synthesis, molecular recognition, and anticancer activity.
The facile synthesis of linear and cyclic chiral oligo(4-alpha/beta-methyl)thiazolines is described. Linear oligothiazolines have been efficiently synthesized by the iterative formation of thiazoline rings and two-directional block condensation. The construction of 24- to 36-membered cyclic oligothiazolines was achieved through the head-to-tail cyclo-oligomerization of doubly deprotected linear fragments. Studies of the interactions of both the linear and cyclic oligomers with chiral compounds revealed that cyclic oligomers displayed a strong binding affinity towards mandelic acid, whereas linear oligomers showed a poor affinity. Linear oligomers have been proven to inhibit the cell growth of the cancer cell lines HPAC, PC-3, and HCT-116. Studies of the structure-activity relationships showed that the IC50 values are clearly dependent on both the length and the terminal functionalities of the linear oligomers. Longer derivatives showed more potent activity (e.g., hexi- and octithiazolines exhibit IC50<1 microM) against all three cancer cell lines. In sharp contrast, cyclic oligomers were inactive to all three cell lines.
Han
Fu She
FS
PRESTO, The Japan Science and Technology Agency, Hongo, Tokyo 113-0033, Japan.
Osajima
Hiroyuki
H
Cheung
Mui
M
Tokuyama
Hidetoshi
H
Fukuyama
Tohru
T
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002470:Cell Survival; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology; D006801:Humans; D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D015394:Molecular Structure; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000473:pathology
D000970:Antineoplastic Agents; D047028:Macrocyclic Compounds; D013844:Thiazoles