Biomedical subjects
Publications and source records attributed to S Martelli.
2-Acetylpyridine-(4-phenylthiosemicarbazone) and its metal (II) complexes have been synthesized and characterized by chemical and spectral methods. They were studied for their antibacterial and antifungal activities in vitro. The ligand and its metal (II) complexes exibited significant activity against a wide spectrum of bacteria and fungi.
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A series of 7-oxo-7H-benzo[e]perimidine-4-carboxamides (4a-f) was synthetized from the corresponding acid (3) and the suitable amines by the "mixed anhydride" method. The amide derivatives were tested for antitumor activity against P 388 leukemia "in vivo". Only the N-[2-(diethylamino)ethyl]-7-oxo-7H-benzo[e]perimidine-4-carboxa mid e (4b) shows borderline antineoplastic activity.
Gallbladder cancer is the fifth of the digestive neoplasms. Diagnosis is often made very late sk that prognosis is really poor. We present 84 patients operated on for gallbladder cancer and 1 for carcinoid. Sixty-eight of them had a complete follow-up.
The pancreatic pseudocyst is a serious complication of acute or chronic pancreatitis. Surgical internal anastomosis can be an adequate solution to this problem. Sixty patients with pancreatic pseudocyst have been referred to our institution in the last 15 years; 47 of them were operated upon. Different techniques were employed according to differences in the pseudocyst wall status and the presence or absence of infection.
A novel group of cytotoxic anthraquinone derivatives, 1-[(aminoalkyl)amino]-4-hydroxy-10-imino-9-anthracenones, has been synthesized. It has been shown that imino analogues of the anthracenediones exhibit diminished ability to generate oxygen radicals. The cytotoxic activity of iminoanthracenones obtained was lower than that of the related quinone carbonyl analogues. One of the obtained imino compounds showed a moderate antileukemic activity in vivo.
A series of model anthraquinones with varying symmetry of pi-electron density distribution have been examined to verify our previous hypothesis concerning the essential role of quinone-singlet oxygen complex formation by asymmetric anthraquinones in their peroxidating properties. Comparison of the results of enzymatic studies using NADH dehydrogenase with those of cyclovoltammetric measurements fully confirmed the assumption that one-electron transfer mediation is facilitated by the preceding quinone-oxygen complex formation. To extend the scope of the molecular determinants of oxygen binding found in our previous studies, CNDO/2 and molecular electrostatic field (MEF) calculations have been performed. It has been concluded that the analysis of molecular electrostatic field as well as the dipole moment components has to be taken into account to judge whether a mutual orientation of the quinone and oxygen molecule can be reached which enables binding to occur. The second important factor is the appropriate symmetry of the quinone outer filled orbitals which assures that binding is not forbidden by the Woodward-Hoffman rules. These characteristics also explain the lack of oxygen binding by some asymmetric anthraquinones. The efficient electron transfer mediation be anthraquinones requires, beside the formation of the intermediate quinone-oxygen complex, effective catalysis of this process by oxidoreductase enzyme. The results obtained with model anthraquinones indicated that compounds with more than one phenolic group and an unsubstituted quinone carbonyl are good NADH dehydrogenase substrates. Imino derivatives and compounds with a reduced number or without free phenolic groups exhibit low affinity towards the enzyme.
A new class of antineoplastic agents, the 5-substituted imidazo[4,5,1-de]acridin-6-ones with an (aminoalkyl)amino group in the side chain, has been made. These compounds were synthesized by reduction of 1-substituted 4-nitroacridin-9(10H)-ones and subsequent reaction of the derived amines with carboxylic acids. Their cytotoxic activity against HeLaS3 cells in tissue culture and in vivo antitumor activity against P388 leukemia in mice was demonstrated. A strict relationship between the antineoplastic activity and the number of methylene spacers between proximal and distal nitrogens in the side chain was established.
A series of 8-substituted 5-[(aminoalkyl)amino]-6H-v-triazolo[4,5,1-de]acridin-6-ones (2), structurally related to the imidazoacridinones (1), was synthesized and tested for cytotoxic and antineoplastic activity. Preliminary biological results indicated that the 8-OH derivatives possess the highest antitumor activity. No relationship has been found between the nature of the C-8 substituent and antitumor activity.
The synthesis of unsymmetrically substituted 1,4-bis[(aminoalkyl)amino]anthracene-9,10-diones bearing one "mitoxantrone side arm" and another (aminoalkyl)amino moiety has been described. These unsymmetrical anthracene-9,10-diones exhibit cytotoxic activity against L1210 leukemia cells and antitumor activity against P388 leukemia in mice.
The effect of the replacement of amino groups, attached to the anthraquinone ring in [(aminoalkyl)amino]-anthraquinones, by an amido function on DNA binding, cytotoxicity, and antileukemic activity has been studied. The corresponding 1,4-bis(aminoalkanamido)-9,10-anthracenediones have been synthesized and examined. It has been concluded that such modification does not exclude the DNA binding and cytotoxicity of mentioned compounds but decreases or abolishes the in vivo antileukemic activity.
A series of benzimidazole-4,7-dione derivatives, bearing substituents at positions 1, 2, 5, and 6 of the benzimidazole ring, has been synthesized and tested for antitumor activity in vivo on P388 leukemia. Some of the synthesized compounds show significant antitumor activity, associated with high toxicity, however. Compounds 7, 18, and 27 show the highest antitumor activity in this series, whereas 17, 19, and 22 are scarcely active. Some hypothetical biological precursors of these quinones are devoid of antitumor activity. Some structure-activity relationships are discussed.
Eleven N-enamine derivatives of daunorubicin and of its 5-imino analogue as well as of doxorubicin have been synthesized and evaluated for antileukemic activity in vitro and in vivo. Comparison of biological activities of examined compounds with other enamine derivatives of daunorubicin, reported earlier by us, has indicated that the optimal activity is shown by N-(1-carboethoxypropen-1-yl-2)daunorubicin.
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The biological properties of two new structural groups of modification products of daunorubicin, the N-glycosyl and enamino derivatives, were investigated. The activities of the compounds were characterized in vitro (yeasts and leukaemia cells) and in vivo (L1210 leukaemia in mice). Among the compounds studied DR-19, N-(1-carboethoxypropen-1-yl)daunorubicin, exhibited activity comparable with that of the parent antibiotic. The correlation coefficients calculated showed good correlation between in vitro tests. In vitro activity and potency (reciprocal of optimal dose) in mice leukaemia were also correlated. However, no correlation between the in vitro activity and activity in mice leukaemia (increase of life span) was observed.
4- and/or 4'-substituted 2,2'-bipyridyl-6-carbothioamides have been synthesized and tested for their activity against P-388 lymphocytic leukemia in mice. Of these, only 4'-nitro-2,2'-bipyridyl-6-carbotioamide (IV c) proved to be active.
The synthesis and dopamine agonist activity of some derivatives of trans-6-methyl-7a,8,9,10,11,11a-hexahydro-7H-pyrrolo[3,2,1-gh]- 4,7-phenanthroline (6a-c) are reported. These compounds can be regarded as analogues of ergoline derivatives with the indole nucleus replaced by indolizine. These congeners have been evaluated as inhibitors of prolactin release in vivo. trans-6-Methyl-8-ethyl-7a,8,9,10,11,11a-hexahydro-7H-pyrrolo[3,2,1-gh]- 4,7-phenanthroline (6b) proved to produce a dose-dependent inhibition of serum prolactin that was almost complete at the highest dose employed. Although effective, this compound was far less potent than bromocriptine. The 8-propyl derivative 6c was weakly active only at very high doses, and the 8-methyl derivative 6a proved to be completely ineffective. trans-4-Propyl-1,2,3,4,4a,5,6,10b-octahydro-4,7-phenanthroline (7), a molecular simplification of hexahydropyrrolo-4,7-phenanthroline, proved to be the most potent among the newly synthesized compounds. These results, taken together with those of previous studies, suggest that the presence of the nitrogen of the indolizine nucleus and the N-7 in the octahydro-4,7-phenanthroline 7 are significant for the interaction with the dopamine receptor involved in the control of prolactin release.
New N-amino acid derivatives of daunorubicin have been obtained by acylation of daunorubicin amino group with alpha, beta, and gamma amino acids and their N,N-dibenzyl derivatives. The results of the antitumor activity determination have evidenced that the change of the amino function position in the daunorubicin derivatives, in relation to that of the parent antibiotic, causes the loss of activity.