Biomedical subjects

G Caravatti

Publications and source records attributed to G Caravatti.

25 records · Page 2Linked to original sources

PubMed1996

In vitro trypanocidal activities of new S-adenosylmethionine decarboxylase inhibitors.

A series of novel aromatic derivatives based on the structure of methylglyoxal bis(guanylhydrazone) (MGBG) was examined for in vitro antitrypanosomal activities and cytotoxicities for human cells. One-third of the compounds tested showed trypanocidal activity at concentrations below 0.5 microM after an incubation period of 72 h. Structure-activity analysis revealed that bicyclic compounds with homocyclic rings and unmodified termini were the most active compounds. Results obtained in three laboratories employing different methods and trypanosome populations consistently ranked compound CGP 40215A highest. This compound had a 50% inhibitory concentration of 0.0045 microM for Trypanosoma brucei rhodesiense, was also active against other trypanosome species, including a multidrug-resistant Trypanosoma brucei brucei, and was significantly less toxic than other compounds tested for a human adenocarcinoma cell line, with a 50% inhibitory concentration of 1.14 mM. The effect of CGP 40215A was time and dose dependent, and low concentrations of the compound required exposure times of > 2 days to exert trypanocidal activity. Compounds were inactive against Leishmania donovani and Trypanosoma cruzi amastigotes in murine macrophages in vitro.

Adenocarcinoma↗

PubMed1995

Modelling study of protein kinase inhibitors: binding mode of staurosporine and origin of the selectivity of CGP 52411.

A model for the binding mode of the potent protein kinase inhibitor staurosporine is proposed. Using the information provided by the crystal structure of the cyclic-AMP-dependent protein kinase, it is suggested that staurosporine, despite a seemingly unrelated chemical structure, exploits the same key hydrogen-bond interactions as ATP, the cofactor of the protein kinases, in its binding mode. The structure-activity relationship of the inhibitor and a docking analysis give strong support to this hypothesis. The selectivity of the dianilinophthalimide inhibitor CGP 52411 towards the EGF-receptor protein tyrosine kinase is rationalized on the basis of the model. It is proposed that this selectivity originates in the occupancy, by one of the anilino moieties of the inhibitor, of the region of the enzyme cleft that normally binds the ribose ring of ATP, which appears to possess a marked lipophilic character in this kinase.

Alkaloids↗

PubMed1993

4-Amidinoindan-1-one 2'-amidinohydrazone: a new potent and selective inhibitor of S-Adenosylmethionine decarboxylase.

Two isomeric amidino-2-acetylpyridine amidinohydrazones, 11 and 12, and 4-amidinoindanone amidinohydrazone, 17, have been synthesized and tested for inhibition of S-adenosylmethionine decarboxylase (SAMDC) and diamine oxidase and for antiproliferative activity against T24 human bladder carcinoma cells. Compound 11 inhibited SAMDC with an IC50 of 10 nM and was 140- and > 500-fold more potent than methylglyoxal bis(guanylhydrazone) (MGBG) and 12, respectively. The difference in potency between 11 and 12 was interpreted with the help of molecular modeling and appeared to be associated with two different low-energy conformations of the compounds. Compound 17 which represents a conformationally constrained analogue of 11, was superior to the latter and MGBG with respect to selective inhibition of SAMDC and antiproliferative activity, and is of interest as a potential anticancer agent and a drug for the treatment of protozoal and Pneumocystis carinii infections.

Adenosylmethionine Decarboxylase↗

PubMed1993

S-adenosylmethionine decarboxylase inhibitors: new aryl and heteroaryl analogues of methylglyoxal bis(guanylhydrazone).

A series of 3-acylbenzamidine (amidino)hydrazones 7a-h, the corresponding (hetero)aromatic congeners 7i-p, and 3,3'-bis-amidino-biaryls 25a-e were synthesized. The hydrazones 7a-p were prepared by conversion of the corresponding acyl nitriles 1a,c-d,i,n-p to the imido esters 3a,c-d,i and the amidines 5a,c-d,h-i, followed by a reaction with aminoguanidine, or vice versa. Similarly, the biaryl 3,3'-dinitriles 23a-e were converted, via the imino esters 24a-c or the imino thioesters 27d-e, to the diamidines 25a-e. These new products are conformationally constrained analogues of methylglyoxal bis(guanylhydrazone) (MGBG). They are up to 100 times more potent as inhibitors of rat liver S-adenosylmethionine decarboxylase (SMDC) and generally less potent inhibitors of rat small intestine diamine oxidase (DAO) than MGBG. Some of these SAMDC inhibitors, e.g., compounds 7a, 7e, 7i, 25a, and 25d, have shown antiproliferative effects against T24 human bladder carcinoma cells. These products, whose structure-activity relationships are discussed, are of interest as potential anticancer agents and drugs for the treatment of protozoal and Pneumocystis carinii infections.

Adenosylmethionine Decarboxylase↗

PubMed1993

Differential inhibition of human secretory and cytosolic phospholipase A2.

The roles and relative contributions of secretory and cytosolic phospholipases A2 in physiology and pathology are not precisely known. In a search for differential inhibitors of these enzymes, which could serve as tools to clarify this issue, we evaluated the potencies of reference compounds and three series of new compounds, viz. substrate analogues, 1,2-amino alcohols and enolized beta-tricarbonyl derivatives, as inhibitors of secretory phospholipase A2 from human polymorphonuclear leukocytes (sPLA2) and of cytosolic phospholipase A2 from human U937 cells (cPLA2). With few exceptions, the compounds selected are potent inhibitors of sPLA2 with IC50 values (concentration inhibiting 50%) in the low micromolar range. Inhibition of cPLA2 was only observed with some phosphate-free substrate analogues, with 1,2-amino alcohols and two of seven reference compounds. These results suggest that inhibition of secretory and of cytosolic phospholipases A2 are independent effects. Several inhibitors could be identified with a marked selectivity for sPLA2.

Amino Alcohols↗

PubMed1992

New S-adenosylmethionine decarboxylase inhibitors with potent antitumor activity.

Methylglyoxal bis(guanylhydrazone) (MGBG) has been studied clinically as an antitumor and antileukemic agent and is recognized as a potent but nonspecific inhibitor of the key polyamine biosynthetic enzyme, S-adenosylmethionine decarboxylase (SAMDC). A series of four SAMDC inhibitors with structural features similar to MGBG have been found to have improved potency and specificity toward the target enzyme, SAMDC. Relative to MGBG, the new derivatives were much more effective in inhibiting partially purified preparations of SAMDC (50% inhibitory concentration, 10 to 100 nM), much less effective at inhibiting diamine oxidase, and inactive toward ornithine decarboxylase. The inhibitors varied relative to MGBG in their ability to compete with spermidine for uptake, with two being similar and two being less effective. Against L1210 leukemic cells and T24 bladder carcinoma cells, the compounds were slightly less effective than MGBG at inhibiting cell growth, with 50% inhibitory concentration values of 1 to 10 microM as compared with 0.5 and 1.1 microM, respectively, for MGBG. Under 50% growth-inhibitory conditions, the inhibitors decreased SAMDC activity, increased ornithine decarboxylase activity and putrescine pools, and markedly depleted spermidine and spermine pools of L1210 cells. At the same time, mitochondrial integrity as assessed by whole-cell pyruvate oxidation and mitochondrial DNA content was not affected as it was with MGBG. At doses less than one tenth that of the maximally tolerated dose, all of the new inhibitors strongly suppressed the growth of B16 melanoma in vivo with minimal weight loss or toxicity. At doses less than one sixth the maximally tolerated dose, they effectively inhibited the growth of T24 human bladder carcinoma xenografts. In these same systems, MGBG showed only marginal antitumor activity. These studies identify two potent and efficacious inhibitors of SAMDC as potential antitumor agents and reaffirm the importance of SAMDC as a target in anticancer drug discovery.

Adenosylmethionine Decarboxylase↗

PubMed1989

A derivative of staurosporine (CGP 41 251) shows selectivity for protein kinase C inhibition and in vitro anti-proliferative as well as in vivo anti-tumor activity.

Analogues of staurosporine were synthesized and their ability to inhibit protein kinases was examined. Staurosporine is a potent but non-selective inhibitor of in vitro protein kinase C(PKC) activity (IC50 6.0 nM). The derivative CGP 41 251 had reduced PKC activity with an IC50 of 50 nM but showed a high degree of selectivity when assayed for inhibition of cyclic AMP-dependent protein kinase (IC50 2.4 microM), S6 kinase (IC50 5.0 microM) and tyrosine-kinase-specific activity of epidermal growth factor receptor (IC50 3.0 microM). Staurosporine and CGP 41 251 exerted growth inhibition in the human bladder carcinoma line T-24, human promyelocytic leukemia line HL-60 and bovine corneal endothelial cells at concentrations which correlated well with in vitro PKC inhibition. In addition, both compounds inhibited the release of H2O2 from human monocytes pre-treated with 12-O-tetradecanoyl-phorbol-13-acetate at non-toxic concentrations. In vivo anti-tumor activity was examined in T-24 human bladder carcinoma xenografts in athymic nude mice. Tumor growth inhibition tests revealed significant anti-tumor activity (2p less than 0.001) at 1/10 of the maximum tolerated doses for both compounds. By contrast, a closely related derivative of staurosporine (CGP 42 700) was inactive at concentrations of over 100 microM in all in vitro enzyme and anti-proliferative assays as well as in animal tumor models. Our data suggest an association between PKC inhibition and anti-proliferative and anti-tumor activity.

Alkaloids↗