2002 Fiscal Year Final Research Report Summary
Structure-Activity-Relationship of Topostatin Derivatives with Cyclic Peptide as Topoisomerase Inhibitor
Grant-in-Aid for Scientific Research (C)
|Allocation Type||Single-year Grants |
|Research Institution||Kumamoto University |
OKAWARA Tadashi Faculty of Pharmaceutical Sciences Associate Professor -> 熊本大学, 薬学部, 助教授 (60040325)
|Project Period (FY)
2001 – 2002
|Keywords||Anti-Cancer Agent / Topoisomerase Inhibitory / Cyclic depsi peptide / Topostatin / aliphatic acid with a long chain / O-sulfonate|
The preparation of topostatin derivatives was studied on the following two fragments: 1) the side chain 2) the cyclic depsipeptide.
1) Retrosynthesis of the side chain
The side chain were divided to four fragments and the preparations of each parts were examined to link together.
Reaction of 2-nonanone with ethyl triethylphosphoate gave α,β-unsaturated ester followed by reduction and oxidation to afford the corresponding aldehyde. Subsequently, Wittig reaction of aldehyde gave 4,7-dimethyltetradeca-2,4-dienoic ester as the side chain. The coupling reaction of the ester with protected 6-bromo-3-hydroxyoctanoic acid derivatives was examined to form the keto compound.
2) Preparation of cyclic depsipeptide
The cyclic depsipeptide was divided into three amino acids and β-lactone. By a solid state synthesis FmocSerOBut was fixed the resin followed by deblocking and coupling with Fmoc-β-ala. The same method was repeated with FmocSerOBut, and finally β-lactone. Lactonization of C-terminal and OH group was examined.
3) The intermediates prepared in process 1) and 2) were assayed for topoisomerase inhibitory activities, but their activities were rather weak than that of topostatin.
The coupling reactions of a side chain with a peptide are being investigated.