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1.
J Med Chem ; 43(13): 2557-65, 2000 Jun 29.
Article in English | MEDLINE | ID: mdl-10891115

ABSTRACT

Prodigiosins (Ps) represent a family of naturally occurring red pigments characterized by a common pyrrolylpyrromethene skeleton. Some members of this family have been shown to possess interesting immunosuppressive properties exerted with a novel mechanism of action, different from that of currently used drugs. In fact, Ps inhibit phosphorylation and activation of JAK-3, a cytoplasmic tyrosine kinase associated with a cell surface receptor component called common gamma-chain, which is exclusive of all IL-2 cytokine family receptors. Blocking common gamma-chain transduction activity results in a potent and specific immunosuppressive activity. With respect to the interesting and unexploited immunomodulating properties of this family of compounds we initiated a medicinal chemistry program aimed at finding novel prodigiosin derivatives with improved immunosuppressive activity and lower toxicity. Utilizing an unprecedented and flexible way of assembling the prodigiosin frame, a number of new derivatives have been prepared and tested leading to the choice of 4-benzyloxy-5-[(5-undecyl-2H-pyrrol-2-ylidene)methyl]-2, 2'-bi-1H-pyrrole (PNU-156804, 16) as a lead immunosuppressant.


Subject(s)
Immunosuppressive Agents/chemical synthesis , Prodigiosin/analogs & derivatives , Pyrroles/chemical synthesis , Animals , Cell Survival/drug effects , Female , Humans , Hypersensitivity, Delayed/drug therapy , Immunosuppressive Agents/chemistry , Immunosuppressive Agents/pharmacology , Immunosuppressive Agents/toxicity , In Vitro Techniques , Lymphocytes/cytology , Lymphocytes/drug effects , Mice , Mice, Inbred C57BL , Prodigiosin/chemical synthesis , Prodigiosin/chemistry , Prodigiosin/pharmacology , Prodigiosin/toxicity , Pyrroles/chemistry , Pyrroles/pharmacology , Pyrroles/toxicity , Spleen/cytology , Spleen/drug effects , Structure-Activity Relationship , Tumor Cells, Cultured
2.
Invest New Drugs ; 14(2): 139-46, 1996.
Article in English | MEDLINE | ID: mdl-8913834

ABSTRACT

The relationship between different chemical modifications on morpholinylanthracyclines and their ability to overcome multidrug resistance (MDR) has been evaluated testing all compounds in vitro on LoVo and LoVo/DX human colon adenocarcinoma cells and in vivo disseminated P388 and P388/DX murine leukemias. Results obtained led us to the following conclusions: 1) the insertion of the morpholinyl or the methoxymorpholinyl group on position 3' of the sugar moiety confers the ability to overcome MDR in vitro and in vivo; conversely, 4' morpholinyl compounds are effective on MDR cells only in vitro and result inactive in vivo on DX-resistant leukemia; 2) all chemical modifications performed on 3' morpholinyl or methoxymorpholinyl derivatives, that is substitutions on the aglycone or on position 2 of the morpholino ring, do not interfere with the activity of the compounds: all derivatives present in fact the same efficacy on sensitive and resistant models. It is concluded that position 3' in the sugar moiety plays a crucial role in the ability of morpholinyl-anthracyclines to overcome MDR.


Subject(s)
Antibiotics, Antineoplastic/pharmacology , Morpholines/pharmacology , Adenocarcinoma/drug therapy , Animals , Antibiotics, Antineoplastic/toxicity , Colonic Neoplasms/drug therapy , Drug Resistance, Multiple , Female , Humans , Leukemia P388/drug therapy , Mice , Mice, Inbred Strains , Morpholines/toxicity , Structure-Activity Relationship , Tumor Cells, Cultured/drug effects
3.
Anticancer Drug Des ; 10(8): 641-53, 1995 Dec.
Article in English | MEDLINE | ID: mdl-8595123

ABSTRACT

New alkylating anthracycline derivatives with promising antitumor activity have been synthesized. We selected two of these compounds, 4-demethoxy-N,N-bis(2 chloroethyl)-4'-methylsulfonyl-daunorubicin (FCE 27726) and 4-demethoxy-3'-deamino-3'aziridinyl-4'-methylsulfonyl daunorubicin (FCE 28729), comparing their interaction with DNA and that of the non-alkylating derivative 4-demethoxy-4'-methylsulfonyl-daunorubicin (FCE 27894). The two alkylating derivatives were more cytotoxic than idarubicin and presented low cross-resistance with doxorubicin. Both FCE 27726 and FCE 28729 were found to alkylate guanines at the N7 position in the major groove with roughly the same specificity, but at different concentrations. FCE 27726 was 10 times more potent than FCE 28729 in alkylating DNA. At higher concentrations, FCE 27726 was able to alkylate adenines, possibly at the N3 position contained in a sequence 5'-PyAA. FCE 27726, as expected, was able to form DNA interstrand cross-links either in vitro and in vivo in treated cells. FCE 28729 did not form DNA interstrand cross-links in vivo. In vitro, at high concentrations, some DNA interstrand cross-links were evident. The non-alkylating derivative FCE 27894 did not produce any alkylation or DNA interstrand cross-links either in vitro or in vivo.


Subject(s)
Antibiotics, Antineoplastic/metabolism , Antineoplastic Agents, Alkylating/metabolism , DNA/metabolism , Animals , Base Sequence , Mice , Tumor Cells, Cultured
4.
Invest New Drugs ; 12(2): 93-7, 1994.
Article in English | MEDLINE | ID: mdl-7860237

ABSTRACT

The objective of the experiments reported in this paper was the identification of promising anthracycline analogs on the basis of lack of cross-resistance against tumor cells presenting either P-glycoprotein multidrug resistance (Pgp-MDR) or the altered topoisomerase multidrug resistant (at-MDR) phenotype. Differently modified anthracycline analogs known to be active against MDR cells were assayed in vitro against CEM human leukemic cells, and the sublines CEM/VLB100 and CEM/VM-1 exhibiting respectively the Pgp-MDR and the at-MDR phenotype. Two classes of molecules, in which the -NH2 group in C-3' position is substituted with a morpholino, methoxymorpholino (morpholinyl-anthracycline), or an alkylating moiety, present equivalent efficacy in the drug-sensitive and the two drug-resistant sublines. These results indicate that such molecules may exert their cytotoxic effect through a mode of action different from that of "classical" anthracyclines and is not mediated through topoisomerase II inhibition. Both molecules represent novel concepts in the field of new anthracyclines derivatives.


Subject(s)
Antibiotics, Antineoplastic/pharmacology , Leukemia/drug therapy , ATP Binding Cassette Transporter, Subfamily B, Member 1/biosynthesis , Antibiotics, Antineoplastic/chemistry , Cell Division/drug effects , DNA Topoisomerases, Type II/metabolism , Drug Resistance, Multiple/physiology , Humans , Structure-Activity Relationship , Tumor Cells, Cultured
5.
Br J Cancer ; 65(5): 703-7, 1992 May.
Article in English | MEDLINE | ID: mdl-1586598

ABSTRACT

FCE 23762 is a new doxorubicin derivative obtained by appending a methoxymorpholinyl group at position 3' of the sugar moiety. The compound is greater than 80 times more potent than doxorubicin, it is highly lipophilic, and presents equivalent anti-tumour activity when administered by i.p., i.v. or oral route. The pattern of anti-tumour activity of FCE 23762 differs from that of doxorubicin in maintaining anti-tumour activity against two P388 murine leukaemia sublines resistant to doxorubicin and, although at borderline levels of efficacy, against LoVo human colon adenocarcinoma resistant to doxorubicin. FCE 23762 exhibits remarkable efficacy against MX-1 human mammary carcinoma, with most treated mice being cured both after i.v. and oral treatment. Anti-tumour activity was also observed against L1210 murine leukaemia and two sublines resistant to cis-platinum and melphalan, M5076 murine reticulosarcoma, MTV murine mammary carcinoma and N592 human small cell lung cancer.


Subject(s)
Doxorubicin/analogs & derivatives , Doxorubicin/pharmacology , Leukemia P388/drug therapy , Neoplasms, Experimental/drug therapy , Animals , Female , Humans , Leukemia P388/pathology , Male , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , Mice, Inbred DBA , Neoplasm Transplantation , Neoplasms, Experimental/pathology , Transplantation, Heterologous , Tumor Cells, Cultured/drug effects
7.
Cancer Chemother Pharmacol ; 10(2): 84-9, 1983.
Article in English | MEDLINE | ID: mdl-6831630

ABSTRACT

New 4'-C-methyl analogues of daunorubicin, synthesized by the coupling reaction of daunomycinone with 1-chloroderivatives of protected 4-C-methyldaunosamine analogues, were chemically transformed to the corresponding doxorubicin analogues. Their cytotoxic effect against HeLa cells, ability to bind to DNA, and in vivo toxicity and antitumor activity were compared with those of daunorubicin, doxorubicin, and their 4'-O-methyl analogues. The cytotoxic effect of the new anthracyclines could be correlated with their ability to bind to DNA and with their toxicity in experimental animals; however, the antitumor effectiveness did not seem to be related to these parameters. In general all the compounds retained a remarkable antitumor activity at their optimal doses. The most active compound against P388 leukemia was 4'-O-methyldoxorubicin, which was also more active than doxorubicin against L1210 leukemia.


Subject(s)
Antibiotics, Antineoplastic/chemical synthesis , DNA/metabolism , Daunorubicin/analogs & derivatives , Doxorubicin/analogs & derivatives , Leukemia, Experimental/drug therapy , Animals , Cell Survival/drug effects , Daunorubicin/toxicity , Doxorubicin/toxicity , HeLa Cells/metabolism , Hexosamines , Humans , Mice , Neoplasm Transplantation , Structure-Activity Relationship
8.
Carbohydr Res ; 58(2): 353-61, 1977 Oct.
Article in English | MEDLINE | ID: mdl-912692

ABSTRACT

The synthesis is described of 3-amino-2,3-dideoxy-L-arabino-hexose (10), methyl 2,3-dideoxy-alpha-L-lyxo-hexopyranoside(17), methyl 3-amino-2,3-dideoxy-alpha-L-ribo-hexopyranoside (21), methyl 2,3-dideoxy-3-trifluoroacetamido-alpha-L-xylo-hexopyranoside (26), and certain derivatives from methyl 4,6-O-benzylidene-2-deoxy-alpha-L-arabino-hexopyranoside (3). Conversion of 2-deoxy-L-arabino-hexose into 3 by modified, standard procedures, and on a large scale, gave a 75% yield.


Subject(s)
Daunorubicin/analogs & derivatives , Daunorubicin/chemical synthesis , Mass Spectrometry , Methods , Optical Rotation , Structure-Activity Relationship
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