Showdomycin analogues: synthesis and antitumor evaluation.

The synthesis of N-beta-D-ribofuranosyl derivatives of maleimide, 3-methylmaleimide, and 3-chloromaleimide was accomplished in three steps from ribosylamine. The synthetic ribosides can be considered N-nucleoside analogues of showdomycin, which is an antitumor antibiotic of the C-nucleoside type. Although the three analogues were cytotoxic to cultured L1210 cells, no in vivo antitumor activity was found with the murine P388 leukemia test system. Drug transport studies were done in an attempt to trace the biological fate of the analogues.

Toxicity quantitative structure--activity relationships of colchicines.

A method for extracting LD50 values from antitumor test data is described. A quantitative structure--activity relationship (QSAR) for 7- and 10-substituted colchicines is presented. This correlation equation closely parallels that which had been derived earlier for potency. This result indicates that attempts to modify 7- and 10-substituted colchicines in order to decrease toxicity will likely produce a simultaneous decrease in potency. Ring A modified colchicines do not obey the potency and toxicity correlations. 4-Substituted colchicines appear promising in terms of decreased toxicity, greater ILS, and a broader therapeutic range.

Quantitative structure-activity relationships of colchicines against P388 leukemia in mice.

A quantitative structure-activity relationship (QSAR) was derived for colchicine and 14 analogues acting against P388 lymphocytic leukemia in mice. Twelve additional compounds were synthesized to reinforce and confirm the correlation. The final correlation indicates that there is a parabolic dependence of antitumor potency on the partition coefficient with log P0=1.17. When an amino nitrogen is present on the B ring, increased potency is favored by acylation of the nitrogen. The most potent compound of the series was the 7-fluoroacetamide analogue. Strong electron-withdrawing groups substituted at the 10 position of the tropolone ring destroy activity. Electron-releasing groups at position 10 improve potency slightly but have a limited effect.

Synthesis and antitumor activity of analogues of the antitumor antibiotic chartreusin.

First isolated in 1953 from a fermentation broth, chartreusin (1) has received renewed interest as a result of substantial antitumor activities recently demonstrated in several murine test systems. Poor water solubility frustrated formulation attempts, and rapid biliary excretion observed in mice made 1 an improbable candidate for clinical development but an excellent candidate for an analogue synthesis program. From a common intermediate, which was prepared from 1, three analogues were synthesized wherein the disaccharide moiety of 1 was systematically replaced with fucose (6), glucose (7), and the disaccharide maltose (8). Each of the three analogues had a cytotoxic potency against cultured L1210 cells which was equal to, or better than, that shown by 1. Based on the structural similarity with the parent, an improved water solubility, and a favorable accessibility through synthesis, maltoside 8 was choe P388 leukemia, 8 showed reproducible activity comparable to chartreusin at similar dose levels. Although 8 caused no observable toxic effects at therapeutic dose levels when given ip, neither 1 nor 8 produced active indications when administered subcutnaeously.

Synthesis of propranolol mustard as a possible lung-specific antitumor agent.

A nitrogen mustard analog of propranolol was synthesized as a potential lung-specific antitumor agent. Since dl-propranolol concentrates in lung tissue and beta-blocking activity resides only with the l-enantiomer, the d-modification could serve as a lung-directed carrier for a cytotoxic group. Reaction of 1-(1-naphthyloxy)-3-[bis(2-hydroxyethyl)amino]-2-propanol with thionyl chloride resulted in replacement of all three hydroxyl groups with chlorine. The necessary chlorination selectivity was achieved with p-toluenesulfonyl chloride in dimethylformamide solution to provide propranolol mustard, 1-(1-naphthyloxy)-3-[bis(2-chloroethyl)amino]-2-propanol. Both the trichloro compound and propranolol mustard showed reproducible activity against P-388 leukemia. Neither compound was active against the B16 tumor or Lewis lung carcinoma.

Usnic acid derivatives as potential antineoplastic agents.

Usnic acid, a lichen antibiotic, showed low-level activity in the Lewis lung carcinoma test system. In an effort to produce new agents of potential use in the treatment of lung cancer, derivatives of the natural product were synthesized and evaluated with a cytotoxicity assay. Structure--activity analysis of the cytotoxicity data indicated the importance of the lipophilicity and the beta-triketone moiety of usnic acid on cytotoxicity. No significant increases in survival of test animals over controls were shown by any of the synthetic compounds in the P388 leukemia or the Lewis lung carcinoma test systems.

Synthesis and antitumor activity of 5-azacytosine arabinoside.

5-Azacytosine arabinoside (ara-AC) can be considered a combination of structural elements derived from the antitumor nucleosides cytosine arabinoside (ara-C) and 5-azacytidine (5-AC). The synthesis of ara-AC, for which standard methods were inadequate, was accomplished using the stable dihydro derivative as a synthetic intermediate. A novel dehydrogenation of the latter through the application of a trimethylsilylation-oxidation procedure gave ara-AC in good yield. Using murine L1210 leukemia as a test system, ara-AC was evaluated for antitumor properties in parallel determinations with 5-AC and ara-C. Although higher dose levels were necessary, ara-AC demonstrated a reproducibly greater efficacy in the L1210 system (% ILS = 144-148) than that shown by 5-AC (% ILS = 126-124) or ara-C (% ILS=127-121 ). Moreover, initial data suggest that ara-AC exhibits less host toxicity than either 5-AC or ARA-C. Although ara-AC can equally be considered an analogue of either 5-AC or ara-C, preliminary results indicate that ara-AC is chemically similar to 5-AC but biologically more closely related to ara-C.

Synthesis and antitumor properties of some isoindolylalkylphosphonium salts.

Antitumor evaluation of 2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyltriphenylphosphonium bromide (1) revealed significant activity in P-388 lymphocytic leukemia (T/C = 160%). As a follow-up to this chemical lead, a series of closely related phosphonium salts was prepared in which the 1,3-dihydro-1,3-dioxo-2H-isoindole ring system was maintained or in which it was replaced by other moieties such as maleimido, bromo, methoxy, and isoindoline. Syntheses generally involved treatment of the appropriate N-(bromoalkyl)phthalimide with the required phosphine or condensation of the K salt of the substituted imide with beta-(bromoethyl)triphenylphosphonium bromide (12). From the biological data obtained for these compounds, several requirements can be defined for substantial antileukemic activity. Of utmost importance is the presence of a triarylphosphonium halide moiety, coupled to an alkyl chain of two or three carbon atoms. The preferred terminus of the alkyl chain is the 1,3-dihydro-1,3-dioxo-2H-isoindole ring system, although the observed activity of beta-(bromoethyl)-triphenylphosphonium bromide (12) (T/C = 127%) would suggest that a superior carrier molecule could be developed.

Isolation, characterization, and properties of a labile hydrolysis product of the antitumor nucleoside, 5-azacytidine.

The antitumor nucleoside, 5-azacytidine (5-AC), is best administered clinically by prolonged intravenous infusion to minimize toxic effects. In opposition to this administration technique is facile drug decomposition in aqueous formulations giving products of unknown toxicity. Analysis of 24-h-old water solutions of 5-AC with high-pressure liquid chromatography (HPLC) indicated a threefold mixture of 5-AC, N-(formylamidino)-N'-beta-D-ribofuranosylurea (RGU-CHO), and 1-beta-D-ribofuranosyl-3-guanylurea (RGU). Preparative HPLC allowed the isolation and subsequent identification of each component in the mixture, including RGU-CHO which until now has not been available for chemical and biological study. It was shown that RGU-CHO in water solution readily equilibrates to 5-AC and more slowly deformylates to give RGU irreversibly. The latter hydrolysis produce exhibited no pronounced toxicity when tested either in vitro or in vivo. Although RGU-CHO showed considerable antitumor activity against murine L1210 leukemia, hydrolysis studies indicated that all of the observed activity could be attributed to 5-AC formed by in vivo equilibration from RGU-CHO. Moreover, RGU-CHO seemed to impart to test animals a toxicity which was no greater than that anticipated from its ability to generate 5-AC.

Comparative studies of the cytostatic action and metabolism of 5-azacytidine and 5,6-dihydro-5-azacytidine.

5,6-Dihydro-5-azacytidine hydrochloride, a chemically stable, soluble analog of 5-azacytidine, has cytostatic activity against mouse leukemic L1210 cells grown in culture, but concentrations on the order of 10 micronM, 10-fold higher, than the parent drug, are necessary to inhibit cell growth. The addition of either cytidine or uridine protected against growth inhibition by 5-azacytidine and 5,6-dihydro-5-azacytidine, whereas thymidine potentiated the cytostatic action of both drugs. Deoxycytidine also enhanced the action of 5-azacytidine but had no effect with the reduced analog. Cell suspensions of L1210 cells were able to phosphorylate 5-azacytidine and, to a lesser extent, 5,6-dihydro-5-azacytidine. In cell-free extracts in the presence of ATP and Mg2+, both drugs were converted to nucleotides but at less than 5% the rate of cytidine. As a substrate for mouse kidney cytidine deaminase, the apparent Km value for 5,6-dihydro-5-azacytidine (33 micronM) is of the same order of magnitude as that for cytidine (37 micronM) but less than that for 5-azacytidine (2.1 X 10(3) micronM). The Vm for deamination of the reduced analog is one-tenth that for 5-azacytidine. 3,4,5,6-Tetrahydrouridine, a potent inhibitor of cytidine deaminase, is more effective in blocking deamination of 5-azacytidine than 5,6-dihydro-5-azacytidine.

Potential antitumor agents: procarbazine analogs and other methylhydrazine derivatives.

With the objective of developing new antitumor agents, two groups of hydrazine compounds, having structural features in common with the antitumor agents procarbazine and 1-acetyl-2-picolinoylhydrazine, were synthesized. The L-1210 leukemia system was used to evaluate compounds of both groups. The aliphatic procarbazines also were screened for antitumor activity as bis(benzyloxycarbonyl) derivatives and as derivatives having a phthalazine nucleus. No L-1210 antitumor activity was exhibited by these compounds.

Antitumor agents II: nitrogen analogs of mycophenolic acid.

Mycophenolic acid, a novel antibiotic of low toxicity containing no nitrogen atoms in its structure, induces tumor regression in several murine solid tumor assays. It has been reported in extensive structure-activity studies that chemical modifications on the antibiotic itself reduce or eliminate antitumor activity. With the objective of antitumor activity enhancement, nitrogen-containing analogs of mycophenolic acid were synthesized according to a program directed toward the ultimate synthesis of close bioisosteres of the antibiotic. Intial efforts reported here describe the terpenoid side-chain degradation of N-geranyl-2(1H)-pyridones and N-geranylglutarimides, where the terminal isopropylidene is replaced with a carboxyl group as it occurs in mycophenolic acid. The resulting nitrogen-containing analogs of the antitumor antibiotic were inactive in the l-1210 and Walker 256 tumor systems.