A series of naturally occurring and synthetic novel oxapenam (4-oxa-1-azabicyclo[3.2.0] heptan-7-one) derivatives with their antitumor activity and the structure-activity relationship among this class of compounds is reported. Among the synthetic 4-oxa-1-azabicyclo[3.2.0]heptan-7-one having an ester, amide, ether derivatives of hydroxy group at C-3 position exhibited either no activity or reduced the antitumor activity in vitro. The 3-amino acid 4-oxa-1-azabicyclo[3.2.0]heptan-7-one derivatives showed better antitumor activity than naturally occurring 4-oxa-1-azabicyclo[3.2.0]heptan-7-one derivative G0069A. The trans isomers exhibited superior stability and activity over the cis isomers at the 3- and 5-position. Some of these compounds showed strong cytotoxicity against P388 and KB cells with IC(50) value ranging from 0.004 to 0.6 micro g/ml and they did not show any cross resistance against ADR, 5-FU and VCR resistant cell lines in vitro. Of these, 3-hydroxy methyl, 3-(2-amino-2-carboxy-1-benzyloxy ethyl) and 3-(2-amino-2-carboxy ethyl) 4-oxa-1-azabicyclo[3.2.0] heptan-7-one inhibited 71-84% in vivo tumor growth of colon 26 and S-180 cells subcutaneously implanted into mice at a varying dose between 0.625-15 mg/kg/day depending upon the compounds and the tumor cell lines.

01 Sep 1997·Yao xue xue bao = Acta pharmaceutica Sinica

[Antitumor activity of the clavam peptide antibiotic G0069A].

Article

Author: Qi, C Q ; Chen, W J ; Zhen, Y S ; Xue, Y C ; Dai, J

Antibiotic G0069A, produced by a Streptomyces strain isolated from a soil sample collected in Yunnan Province, China, has been verified as a clavam peptide. Determined by MTT assay, G0069A showed highly potent cytotoxicity to cancer cells with multidrug resistance. The IC50 values of G0069A to KB and KB/VCR cells were 0.60 and 0.46 mumol.L-1, and to MCF-7 and MCF-7/ADM cells were 1.4 and 1.2 mumol.L-1, respectively. G0069A displayed equally potent cytotoxicity to the parent cell lines and their resistant sublines. When administered by i.v. or i.p. route at tolerable doses, G0069A exhibited markedly inhibitory effect on the growth of sarcoma 180 and hepatoma 22 in mice. At dose level of 3 mg.kg-1, i.v., x3, sarcoma 180 and hepatoma 22 were suppressed by 87%(P < 0.01) and 72%(P < 0.01), respectively. The results indicate that G0069A is a beta-lactam antibiotic showing antitumor activity.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	Canada	NAEJA-RGM Pharmaceutical, Inc.	-

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