Potential coanthracyclinic activity of pyridylmethylene-2-indolinones.

The paper reports the cytotoxic activity of pyridylmethylene-2-indolinones previously described as cardiotonics and the synthesis of three analogs of the most potent cytotoxic agent. Some of these compounds could be useful, when associated with anthracyclines, to reduce the cardiotoxicity of these potent antitumor drugs.

In vivo cardiotonic activity of pyridylmethylene-2-indolinones.

The synthesis of 5-chloro-3-pyridylmethylene-2-indolinone is reported. This compound was subjected to an in vivo cardiotonic assay with 10 analogs whose synthesis and in vitro cardiotonic activity were previously reported. All the compounds tested (except the 5-hydroxyindole derivative) showed significant positive inotropic activity. The 3-pyridyl derivative without substituents at the indole system was the most active of the whole series.

Synthesis and cytotoxic activity of new peptides containing basic amino acid residues.

In search of more potent compounds endowed with a cytotoxic activity, a new series of basic peptides was synthesized using solid-phase methods. All peptides were purified by preparative reverse-phase HPLC and characterized by electrospray mass spectrometry. The cytotoxic activity was determined in cultured HeLa cells. The hexadecapeptides 5 and 6 showed a 50% inhibition at the concentration of 30 micrograms/ml. The salmina and the polyamino acids of L-arginine, L-histidine and L-lysine, containing sixteen residues, were virtually inactive. This demonstrates that a specific peptide sequence is necessary to obtain a positive response in HeLa test.

In vivo cardiotonic activity of aryl- and pyridyl-substituted fused imidazoles.

Two new imidazo[2,1-b]thiazoles related to sulmazole were synthesized and subjected to an in vivo cardiotonic assay with 14 analog compounds which gave the best results in previously reported in vitro tests. The data obtained show that three substituents (3-pyridyl, 4-pyridyl and 2,5-dimethoxyphenyl group) are useful pharmacophoric groups in modulating the in vivo cardiotonic activity of the fused imidazoles considered.

Enhancement of cytotoxic activity by synthesis of peptide multimeric forms.

Synthesis of four multimeric H-Lys-His-His-Arg-Lys-Lys-His-Arg-Lys-Arg-Lys-His-His-Lys-Arg-Lys-oH peptides containing two, four, eight and sixteen branches was carried out by solid phase utilizing a lysine core matrix. These multimeric peptides enhanced activity by inhibiting the colony-forming ability of HeLa cells, from twenty-four to fifty-six times in comparison with the monomeric form. Unexpectedly the peptide with only two-branched sequences showed the highest inhibitory activity.

Role of chemotherapeutic antagonism in opportunistic infections.

The most widely-known anti-tumor drugs often induce marked immunosuppression which can give rise to one or more sepses. Anti-infection measures immediately applied can sometimes prove largely ineffective or even useless, the patient dying not as a result of the spread of the tumour but as a direct consequence of opportunistic infection. We postulate that antagonism between anti-tumour and antimicrobial drugs may also play an important part in this. By way of illustration of this hypothesis, we have studied the action of a number of known inhibitors of peptidoglycan synthesis and of DNA-gyrases on certain strains of Gram-positive and Gram-negative microorganisms cultured in medium containing various concentrations of some of the best-known anti-tumour antimetabolites. The experimental data show that antimicrobial and anti-tumour drugs can sometimes induce synergic or indifferent chemotherapeutic interactions with many bacteria, while in others the effect is antagonistic. In practice, the action of the drugs could lead to bacterial selectivity, which, in conjunction with immunosuppression and the presence of resistant strains, could favour the evolution of opportunistic infection.

Potential antitumor agents. 25 [1]. Synthesis and cytotoxic activity of 3-(2-chloro-3-indolylmethylene)1,3-dihydroindol-2-ones.

The Knoevenagel reaction between 2-indolinones and 2-chloroindolaldehydes gave 3-(2-chloro-3-indolylmethylene)1,3-dihydroindol-2-ones which were tested as potential antitumor agents on cultures of HeLa cells. 2-Chloro derivatives with at least one unsubstituted NH group, are promising candidates for further investigation.

Influence of antimalarials chloroquine, quinine, primaquine and mepacrine on the evolution of Ehrlich ascites tumour.

Substances like imidazoles, benzimidazoles and also quinolines, whose chemical structure includes a heterocyclic nitrogen, are known to interfere with the microsomal oxidation and, in some cases, with the metabolism of drugs. Since chloroquine and primaquine exert this effect in vivo and in vitro, we studied the influence of other antimalarials (quinine and mepacrine) in mice with induced Ehrlich ascites tumour (EAT) to find out whether variations in oxygen consumption affected the course of the disease. In vitro data, obtained by a polarographic technique, indicate that primaquine and, in particular, mepacrine increase EAT-cell oxygen consumption, while in vivo data, obtained in mice injected with an inoculum of about 1 x 10(6) tumour cells per mouse, show that both drugs, but notably mepacrine, accelerate tumour growth, as monitored by Cox's statistical method for body weight, and lead to earlier death. In cases of existing neoplasia, therefore, the potentially toxic effects of certain antimalarials must be borne in mind.

Antitumor activity of an alkylating derivative of dipyridamole.

Synthesis of 2,6-Bis[bis(2-chloroethyl)amino]-4,8-dipiperidino-pyrimido [5,4-d]pyrimidine (DIP-C1) was carried out, and the new derivative showed cytotoxic activity comparable to other alkylating drugs on cultured P388 leukaemia cells and HeLa cells. The present paper reports the effects of DIP-C1 on respiration of Ehrlich ascites tumor cells and on survival of the mice implanted with Ehrlich ascites tumor cells. The compound showed a significant activity in both experimental models.

Potential antitumor agents. 24. Synthesis and pharmacological behavior of imidazo[2,1-b]thiazole guanylhydrazones bearing at least one chlorine.

In connection with a previous research dealing with the antitumor activity of imidazo[2,1-b]-thiazole guanylhydrazones, this paper reports the synthesis of new derivatives which were tested for antitumor and positive inotropic activity. In most cases the cytotoxic data from the in vitro experiments (HeLa) were in agreement with the antitumor data in vivo (Ehrlich). The active compounds bear a phenyl ring at the 6 position. On the other hand, the most active cardiotonic agents were devoid of the phenyl ring.

Synthesis and cytotoxic activity of peptides containing basic amino acids residues.

We synthesized eight peptides containing from three to twenty residues of arginine, lysine and histidine, using an automated synthetiser and Fmoc strategy. All peptides were purified by preparative reverse-phase HPLC and characterized by electrospay mass spectometry. Cytotoxic activity was assessed on HeLa cells. One peptide inhibited the colony-forming ability of tumor cells.

Reduction of adriamycin cardiotoxicity by enoximone.

Several non catecholamine, non glycoside cardiotonic drugs have been described recently. New compounds include amrinone, sulmazole, milrinone and pimobendan. In an attempt to alleviate or prevent anthracycline toxicity, we have reported that these compounds reduce the negative effects of adriamycin, 4-epiadriamycin and esorubicin in isolated guinea pig atria. The present study reports the effects of a new cardiotonic agent: enoximone. Enoximone was administered after adriamycin (100 micrograms/ml) on the isolated and spontaneously beating atria, and on electrically driven left atria of guinea pig-in normodynamic and hypodynamic conditions. Exposure for 60 minutes to the antitumor drug causes a depression of contractile force (g) and its derivative versus time (dF/dt, as maximal rate of contractile force). The negative effects of adriamycin are antagonised by enoximone (100, 200 micrograms/ml).

In vitro activity of trimethoprim in association with sulfimidazole against aerobic gram-negative and gram-positive microorganisms and Clostridia.

The in vitro activity of a chemotherapeutic agent, sulfimidazole (SIZ), obtained by combining two molecules belonging to groups of extremely different antibacterial drugs, p-aminobenzene sulfonamide and a derivative with a 5-nitroimidazole ring, was studied. In association with trimethoprim, SIZ induces an intense synergistic antibacterial effect on gram-negative and gram-positive aerobic microorganisms and Clostridia. The results show that, in SIZ, the activity of each starting molecule remains unchanged providing that its structure-action relationship is kept intact.

Influence of glycyrrhizin on the evolution and respiration of Ehrlich ascites tumour cells.

It has been demonstrated that 18 alpha-glycyrrhetinic acid, 18 beta-glycyrrhetinic acid and glycyrrhizin effectively inhibit the inception and growth of skin tumours. Moreover, glycyrrhizin and its aglycone act on the growth and differentiation of mouse melanoma cells in culture. In this study we investigated the effect of glycyrrhizin, 18 alpha- and 18 beta-glycyrrhetinic acids on the evolution of Ehrlich ascites tumour in mice. A prolonged glycyrrhizin treatment proved to be effective in modifying the animals' survival pattern.

The effects of roxatidine on neuromuscular transmission.

We have investigated the effects of the H2 receptor antagonist roxatidine on the neuromuscular transmission by using the sciatic nerve-gastrocnemius muscle preparation of the rat in vivo. Roxatidine, administered by i.v. injection, potentiates the neuromuscular blockade induced by d-tubocurarine, pancuronium and aminoglycoside antibiotic, kanamycin. Moreover, the drug alone is capable of producing a blockade on the preparation stimulated at high frequency. The neuromuscular blockade induced by roxatidine is partially reversed by 4-aminopyridine but not by dimaprit.

Antitumor and cardiotonic activity of imidazo[2,1-b]thiazole guanylhydrazones.

A number of imidazo[2,1-b]thiazole guanylhydrazones, whose antitumor activity has already been described, were tested as potential cardiotonic agents. The guanylhydrazone of 2,3-dihydro-6-chloroimidazo[2,1-b]thiazole-5-carboxaldehyde (2a) was the most interesting compound showing both antitumor and cardiotonic activity.

Glycyrrhizin and 18 beta-glycyrrhetinic acid: a comparative study of the pharmacological effects induced in the rat after prolonged oral treatment.

Recent clinical and toxicological studies have investigated the mineralcorticoid-like and hypertensive effects of liquorice, and we therefore set out to identify the active component responsible for these effects. We conducted a 30-day comparative analysis of glycyrrhizin and 18 beta-glycyrrhetinic acid and found that the latter causes significant variations both in systolic blood pressure and in the excretion in the urine of Ca++. The effects were fully reversible on suspension of treatment.

Potential antitumor agents. 23.(1) Cytotoxic and differentiating activity of compounds related to hexamethylenebisacetamide.

The synthesis of potential differentiating agents related to hexamethylenebisacetamide (HMBA) is reported. 1,6-Bis(3,3-dimethyl-2-oxo-2,3-dihydroindol-1-yl)hexane (4) and 1,6-bis(4-carbamoyl-thiazol-2-yl)hexane (9) were not soluble enough to allow biological testing. For this reason the dipotassium salt (10) of 1,6-bis(4-carboxy-thiazol-2-yl)hexane (11) was prepared. The salt 10, tested in the human rhabdomyosarcoma cell line (RMZ) and in the murine Friend erythroleukemia cells (MEL), proved more cytotoxic than HMBA, but was devoid of differentiating activity. Compounds 4, 9, 10 and 11, tested on HeLa cells (in vitro) and on Ehrlich ascites (in vivo) did not show antitumor activity.

Potential antitumor agents. XXII. Synthesis and cytotoxic activity of imidazo [2,1-b]thiazole adamantylthioureas.

A series of imidazo[2,1-b]thiazole adamantylthioureas (3a-f) was synthesized by reaction of the methylsulfanylethylamines 2a-f (prepared in turn from the hydroxymethylimidazo[2,1-b]thiazoles 1a-f and cysteamine) with 1-adamantylisothiocyanate. 1-Adamant-1-yl-3-[2-(6-chloro-2,3- dihydroimidazo[2,1-b]thiazol-5-ylmethylsulfanyl)ethyl] thiourea (3d) was significantly active.

Potential antitumor agents. XX (1). 6-Anilinoimidazo[2,1-b]thiazoles.

The synthesis of 6-anilinoimidazo[2,1-b]thiazoles, related to the well-known antitumor agent amsacrine, is reported. The cytotoxic activity of the new compounds was evaluated on HeLa cells. Compound 3a, the most closely related to amsacrine, was significantly active.