Synthesis and antitumor activity of spergualin analogues. III. Novel method for synthesis of optically active 15-deoxyspergualin and 15-deoxy-11-O-methylspergualin.
Optically active 15-deoxyspergualin (II) and 15-deoxy-11-O-methylspergualin (IIa) were synthesized, and their antitumor activities were examined. The (-)-enantiomers of both II and IIa were active against mouse leukemia L1210, while the (+)-enantiomers were almost inactive. The optical resolution of the key intermediate, (+/-)-N-(7-guanidinoheptanoyl)-alpha-alkoxyglycine (VI) was achieved by use of an exopeptidase, serine (acid) carboxypeptidase [EC 3.4.16.1] and (+/-)-N-(7-guanidinoheptanoyl)-alpha-alkoxyglycyl-L-amino acid (VIII) as the substrate. Considering the enzymatic susceptibility of the substrate (VIII), we deduced that the absolute configuration of the carbon at 11 (C-11) of the bioactive (-)-enantiomer, and so that of natural spergualin (I), is S. This is, to our knowledge, the first report of the use of carboxypeptidase for the resolution of N-acyl amino acid.
Umeda
Y
Y
Central Research Laboratory, Takara Shuzo Co., Ltd., Shiga-ken, Japan.
Moriguchi
M
M
Ikai
K
K
Kuroda
H
H
Nakamura
T
T
Fujii
A
A
Takeuchi
T
T
Umezawa
H
H
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000627:therapeutic use; D006146:Guanidines / Q000138:chemical synthesis / Q000627:therapeutic use; D007939:Leukemia L1210 / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D051379:Mice
D000903:Antibiotics, Antineoplastic; D006146:Guanidines; C076911:methyldeoxyspergualin; C033797:spergualin; C037258:gusperimus