Synthesis, conformational analysis and bioactivity of Lan-7, a lanthionine analog of TT-232.
A sandostatin analog, TT-232 (D-Phe-c[Cys-Tyr-D-Trp-Lys-Cys]-Thr-NH2), exhibits strong antitumor effects both in vitro and in vivo. In order to study the structure-activity relationships of TT-232, we designed and synthesized an analog of TT-232, namely Lan-7, in which the disulfide bridge is replaced by a lanthionine monosulfide bridge. Conformational analysis by NMR spectroscopy and computer simulations revealed that Lan-7 and TT-232 adopt very similar conformations in solution, which are quite different from the preferred conformations of sandostatin. Lan-7 has significant growth inhibition effects on a number of human tumor cell lines. It can also induce apoptosis in human ovarian carcinoma 2008 cells. At the same time, Lan-7 produced no toxicity to normal human hematopoietic progenitor cells. All of these results indicate that the modification we made does not alter the anti-tumor activity of TT-232.
Li
H
H
Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla 92093-0343, USA.
Jiang
X
X
Howell
S B
SB
Goodman
M
M
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000494:pharmacology; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013696:Temperature
D000970:Antineoplastic Agents; C117292:Lan-7; D010456:Peptides, Cyclic; C094462:TT2-32; D013004:Somatostatin