A. Papageorgiou

Synthesis and antitumor activity of a novel diplatinum complex of the binucleating naphthazarinato ligand

Abstract In trying to combine the pharmacological properties of cisplatin and adriamycine, the representative prototypes of the two very active and most used groups of cytotoxic drugs, namely the cis -platinum(II) series and the anthracycline cytostatic antibiotics, we came on the idea to use as ligand for cisplatin molecules the binucleating naphthazarinato moiety, knowing that the naphthoquinone part of the anthracycline molecule is essential for the antineoplastic activity. Synthesis was carried out by the reaction of naphthazarine with K 2 PtCl 4 in the presence of ammonia. This reaction gives a binuclear complex with the stoichiometry Pt 2 (C 10 H 4 O 4 )(NH 3 ) 2 Cl 2 and a planar structure confirmed by IR and electronic spectra. The complex has a very potent antineoplastic activity comparable with that of cisplatin, but much lower nephrotoxicity. The activity spectrum on transplantable tumors is similar to that of cisplatin.

Comparative study of SCE induction and cytostatic effects by homo-azasteroidal esters of N,N-bis(2-chloroethyl)aminobenzoic acid in human lymphocytes

The effect of homo-azasteroidal esters of benzoic acid mustard isomers and the 4-methyl derivatives, which have steroidal lactams as a biological basis, on cytogenetic damage was studied. Twenty compounds were comparatively studied, on a molar basis, as regards their ability to induce sister-chromatid exchanges (SCEs) and cell division delays. A correlation between potency for SCE induction, effectiveness in cell division delay and previously established antitumor activity of these compounds was observed.

Potential Antitumor Agents: Steroidal Amidoesters with an Alkylating Moiety

17 beta-Acetamido-5-androsten-3 beta-ol-p-bis(2-chloroethyl) aminophenylacetate and 17 beta-acetamido-5 alpha-androstan-3 beta-ol-p-bis(2-chloroethyl)aminophenylacetate, amido steroidal alkylating agents, were investigated in L1210 and P388 leukemias, Ehrlich ascites tumor, and adenocarcinoma CA-755. Both substances were determined to increase the life span of the tumor-bearing animals and to cause several long-term survivors in adenocarcinoma CA-755.

4-Aroyl-1-nitrosohydrazinecarboxamides: Synthesis, in vivo and in vitro antitumor activity

Abstract 4-Benzoyl-1-(2-chloroethyl)-1-nitrosohydrazinecarboxamide (I), 1-(2-chloroethyl)-1-nitroso-4-phenylacetylhydrazinecarboxamide (II), 1-(2-chloroethyl)-4-(2-hydroxybenzoyl)-1-nitrosohydrazinecarboxamide (III), 4-(4-aminobenzoyl)-1-(2-chloroethyl)-1-nitrosohydrazinecarboxamide (IV), 4-(4-chlorobenzoyl)-1-(2-chloroethyl)-1-nitrosohydrazinecarboxamide (V), all novel class nitrosoureas, were synthesized. All five compounds showed a dose-dependent activity against leukemias L1210, P388 and Ehrlich ascites tumor (EAT). Compound I was superior, yielding T/C% values of 400%, resulting in many cures, reaching 100% in EAT mice. The effect of the above substances on the incorporation of radioactive precursors into DNA, RNA and proteins of EAT cells was investigated. It was found that treatment of cells with 50 μg/ml of the compounds causes significant inhibition (approximately 70%) of the incorporation of 3H-thymidine into DNA. Finally, the effect of these compounds on sister chromatid exchange (SCE) values and on cell kinetics in cultured human lymphocytes was studied. Compound I was found to be the most effective in causing markedly increased SCE values and cell division delays.

Further studies on the antineoplastic activity of homo-aza-steroidal esters.

The modified steroidal alkylating agents, 17 beta-hydroxy-3-aza-A-homo-4 alpha-androsten-4- one(p-[bis(2-chloroethyl)amino]phenyl)butyrate(1),3 alpha-hydroxy- 13,17-seco-5 alpha- butyrate(2),3 beta-hydroxy-13,17-seco-5-androsten-17-oic- 13,17-lactam(p-[bis-(2-chloroethyl)amino]phenyl)butyrate(3) and and (p-[bis(2-chloroethyl)amino]phenyl)butyric acid(4) have been tested against L1210, P388, Ehrlich ascites tumors (EAT), Lewis lung (LL) carcinoma and adenocarcinoma CA-755. Of four compounds evaluated in L1210 leukemia, none displayed antileukemic activity. Almost all of the four compounds were more or less active against P388 leukemia. Compound 2 possesses a slight antitumor activity in EAT, while only compound 1 appears to be active in LL carcinoma. The antitumor activity of the three modified steroidal esters on adenocarcinoma CA-755 seems to be interesting.

Comparative study on cytogenetic damage induced by homo-aza-steroidal esters in human lymphocytes.

The effect of P[N,N-bis(2-chloroethyl)amino]phenylacetate esters of 3 beta-hydroxy-N-methyl-17 alpha-aza-D-homo-5 alpha-androstan-17-one (compound 3) and 3 beta-hydroxy-17 alpha-aza-D-homo-5 alpha-androstane (compound 2) on sister-chromatid exchange (SCE) frequencies and on human lymphocytes proliferation kinetics was studied. The results are compared with those of the P[N,N-bis(2-chloroethyl)amino]phenylacetate esters of 3 beta-hydroxy-17 alpha-aza-D-homo-5 alpha-androstan-17-one (compound 1). All compounds were found to be active in inducing markedly increased SCE rates and cell division delays. A correlation between potency for SCE induction, effectiveness in cell division delay and previously established antitumour activity of these compounds was observed.