[Hemisynthesis of antineoplastic conjugates with nitrogen-mustard proteins]. / Hémisynthèse de conjugués oncostatiques du type moutardes azotées-protéines.

The synthesis of new conjugates with inhibitory action on tumour growth is investigated by linking amino functions of proteins compounds (lysozyme and alpha s-casein) through an amide linkage at the carboxylic function of nitrogen mustards (chlorambucil and melphalan). The polychlorambucil amides of lysozyme and alpha s-casein derivatives prepared showed experimental antitumour activity when these conjugates were screened against the experimental P388 leukemia. In the case of the conjugates lysozyme-melphalan, an antitumour activity is observed when the amino function of the drug is combined with the carboxylic functions of the protein contrary to the situation of the free amino function of the drug described into the literature.

[Reaction of carbodiimide for the introduction of p-bis(2-chloroethyl)amino-L-phenylalanine to lysozyme]. / Réaction à la carbodiimide visant l'introduction de la p-bis-(2-chloroéthyl)amino-L-phénylalanine sur le lysozyme.

In the synthesis of new prodrugs with inhibitoring action of tumour growth, a new nitrogen mustard derivative was obtained, proceeding of the coupling between an egg-white lysozyme with an antitumor amine nucleophile, the methyl ester of p-bis-(2-chloroethyl)amino-L-phenylalanine (Melphalan), catalyzed by 1-ethyl-3-[3-(dimethylamino)propyl] carbodiimide (EDC), at pH 5.0 and room temperature. In that case, the mechanism for the modification isn't selective of Asp101 in lysozyme. As in cases of histamine and D-glucosamine [3], it is evident that Melphalan is one type of amine who doesn't cause a selective modification of Asp101 but causes somewhat random reaction, because Asp101 is modified followed by modifications of other carboxyls. In this case, we suggest that the amine (Melphalan) may also bind to the substrate binding site in competition with EDC. With this type of amine, enzyme-nucleophile interactions predominate, and the selective activation of Asp101 by EDC is reduced to lead a more random reaction.

Antitumor activity in the acridine series.

The antitumor effect against experimental tumors in mice of three acridine derivatives analog or homolog of N-[4'-(9-acridinylamino)-3'-methoxyphenyl]-methanesulfonamide has been investigated. The 3,6-bis-dimethylamino analog (DAMSA) showed important antitumor effect in murine leukemias and moderate effect in a solid tumor, the M5076 reticulosarcoma. The body weight loss of the treated mice was always within an acceptable range when 100 mg/kg were administered under the conditions of the experiment. However, a systemic toxic effect could be observed when 200 mg/kg were used. This preliminary data may be considered as an important step in the development of new acridine analogs with a different spectrum of antitumor activity.

[Carbon 13 nuclear magnetic resonance conformation studies of peptides with analgesic activity]. / Etude conformationnelle par résonance magnétique nucléaire du carbone 13 de peptides à activité antalgique.

13C Nuclear magnetic resonance studies of proline peptides with central antalgic activity (Pro-Arg, Arg-Pro, Pro-Arg-Pro, Pro-Lys-Pro) indicate a predominance of trans conformation at all pH values; but their physiological activities appear to be related to the ability of the C-terminal proline peptides to assume the cis conformation.