ABSTRACT
Cancer is a serious worldwide health threat, killing almost seven million people per year. Quinones are an important class of antitumour agents that are activated by tumour hypoxia. Primin (2-methoxy-6-n-pentyl-1,4-benzo-quinone), a naturally-occurring product obtained from Primula obconica (Primulaceae) has shown antimicrobial and antitumour properties. The synthesis of the Primin to obtain 3-, 5- or 6-alkyl substituted derivatives has been previously attempted seeking antitumour activity. The intermediate reaction products, 2-methoxy-hydroquinone-di-(2'-tetrahydro-pyranyl) ether and 2-methoxy-6-n-pentyl-hydroquinone-di-(2'-tetrahydropyranyl) ether were obtained and evaluated against sarcoma 180 (S-180) and Ehrlich carcinoma, as well as toxicity tests were performed. The antitumour activity tests showed that these intermediate compounds were able to inhibit S-180 sarcoma and Ehrlich carcinoma growth in mice. These results indicated that the tetrahydropyranyl protect group conserved the antitumour activity in comparison with quinone group, however, it exhibited a less toxic effect, with no characteristic of quinones. These results can suggest that compound 2-methoxy-6-n-pentyl-hydroquinone-di-(2'-tetrahydropyranyl) ether may act as a prodrug with some advantages in comparison with the Primin.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Benzoquinones/chemistry , Benzoquinones/pharmacology , Animals , Antineoplastic Agents/chemistry , Behavior, Animal/drug effects , Benzoquinones/chemical synthesis , Male , Mice , Molecular Structure , Neoplasm Transplantation , Neoplasms/drug therapy , Neoplasms/pathology , Structure-Activity Relationship , Time FactorsABSTRACT
The synthesis of analogs of the C-terminal tridecapeptide of gastrin is described. These pseudopeptide analogs were obtained either by replacing the C-terminal phenylalanine amide with 2-phenylethylalcohol or with 2-phenylethylamine, or by replacing the peptide bond between Trp and Leu, or between Leu and Asp with an aminomethylene (CH2NH). The ability of these compounds to stimulate gastric acid secretion in anesthetized rats and to inhibit binding of labeled CCK-8 to isolated cells from rabbit fundic mucosa was tested. [desPhe13, Leu11]-HG-12-I-beta-phenylethylester 33, [desPhe13, Leu11]-HG-12-II-beta-phenylethylester 38, [desPhe13, Leu11]-HG-12-I-beta-phenylethylamide 32, and [desPhe13, Leu11]-HG-12-II-beta-phenylethylamide 37 acted as gastrin receptor antagonists, while [Trp10-psi(CH2NH)-Leu11]-HG-13-I 31 and [Trp10-psi(CH2NH)-Leu11]-HG-13-II 36 acted as agonists. Unexpectedly, [Leu11-psi(CH2NH)-Asp12]-HG-13-I 30 and [Leu11-psi (CH2NH)-Asp12]-HG-13-II 35 were almost devoid of affinity for the gastrin receptor.
Subject(s)
Gastrins/biosynthesis , Gastric Acid/metabolism , Gastrins/chemistry , Humans , Peptide Biosynthesis , Receptors, Cholecystokinin/antagonists & inhibitorsABSTRACT
The synthesis of analogs of the C-terminal tridecapeptide of gastrin in described. These pseudopeptide analogs were obtained either by replacing the C-terminal phenylalanine amide with 2-phenylethytalcohol or with 2-phenylethylamine, or by replacing the peptid bond between Trp and Leu, or between Leu and Asp with an aminomethylene (CH2NH). The ability of these compounds to stimulate gastric acid secretion in anesthetized rats and to inhibit binding of labeled CCK-8 to isolated cells from rabbit fundic mucosa was tested. [desPhe13, Leu11]-HG-12-I-beta-phenylethylester 33, [desPhe13, Leu11]-HG-12-II-beta-phenylethylester 38 [desPhe13, Leu11]-HG-12-I-beta-phenylethylamide 32, and [desPhe13, Leu11]-HG-12-II-beta-phenylethylamide 37 acted as gastrin receptor antagonists, while [Trp10-((CH2NH)-Leu11]-HG-13-I 31 and (Trp10-((CH2NH)-Leu11]-HG-13-II 36 acted as agonists. Unexpectedly, [Leu11-((CH2NH)-Asp12]-HG-13-I 30 and [Leu11-((CH2NH)-Asp12]-HG-13-II 35 were almost devoid of affinity for the gastrin receptor.