Synthesis of 9-acridinyl sulfur derivatives: sulfides, sulfoxides and sulfones. Comparison of their activity on tumour cells.

The synthesis of several acridine thioethers is described. These compounds were oxidized to give new sulfoxides and sulfones. Among 23 compounds prepared, 19 were tested in vitro against the human cancer cell lines panel of NCI screening. Activity is increased 5-10 times from sulfides to sulfoxides. Among substituted groups in the side chain, sulfur mustard, epoxy sulfide and sulfoxide displayed the most interesting activity.

Polymorphism in plasmodium falciparum drug transporter proteins and reversal of in vitro chloroquine resistance by a 9,10-dihydroethanoanthracene derivative.

BG958 reverses resistance in chloroquine-resistant isolates from different countries. Five mutations in the Plasmodium falciparum crt (pfcrt) gene resulting in the amino acid changes K76T, M74I, N75E, A220S, and R371I are systematically identified in resistance-reversed Asian, African, and Brazilian parasites which possess the pfcrt (CIET) haplotype. In combination with BG958, the activity of chloroquine is increased in parasites with the N86Y mutation in pfmdr1.

Arylsulfonyl acridinyl derivatives acting on Plasmodium falciparum.

Several arylacridinyl sulfones have been synthesized and their antimalarial action was tested on Plasmodium falciparum. PABA (para-aminobenzoic acid) has no antagonistic effect with these compounds as opposed to the observed effect with dapsone and sulfonamides previously studied. A possible relationship between the ability of cleavage of the S-9C acridinic bond and activity is suggested.

Dihydroethanoanthracene derivatives as in vitro malarial chloroquine resistance reversal agents.

The ability of four 9,10-dihydroethanoanthracene derivatives (BG920, BG932, BG958, and BG996), as well as verapamil and promethazine, to reverse chloroquine resistance was assessed against 24 chloroquine-resistant and 10 chloroquine-susceptible strains of Plasmodium falciparum from different countries. The 9,10-dihydroethanoanthracene derivatives clearly increase chloroquine susceptibility only in chloroquine-resistant isolates.

Effects of a series of dihydroanthracene derivatives on drug efflux in multidrug resistant cancer cells.

A set of 9,10-dihydro-9,10-ethano and ethenoanthracene derivatives was tested with the aim to quantify the effect observed on drug efflux. Structure activity relationships and molecular modeling studies allowed to define topological display of pharmacophoric groups for these reversal agents.

Synthesis of aza mono, bi and tricyclic compounds. Evaluation of their anti MDR activity.

Anti MDR activity of a series of acridine, pyridoquinoline, quinoline and pyridine analogous amines was evaluated. Interesting activity is displayed by tricyclic compounds. Besides ring size, influence of the side chain was studied.

In vitro reversal of chloroquine resistance in Plasmodium falciparum with dihydroethanoanthracene derivatives.

The effects of combining four dihydroethanoanthracenic (DEA) derivatives and chloroquine were assessed in vitro against Plasmodium falciparum chloroquine resistant parasites W2, Palo Alto, FCR3, and Bres1. Like verapamil or promethazine, the four dihydroethanoanthracenic derivatives tested can be added to the growing list of agents that show capability in enhancing the activity of chloroquine against resistant parasites. The structurally related tricyclic antihistaminic compounds examined in this study exerted different intrinsic antimalarial activity, but the same chloroquine-potentiating activity as verapamil or promethazine. They may act both on the rate of chloroquine accumulation and on its access to ferriprotoporphyrin IX. The reversal mechanism would be assumed to result from competition between DEA derivatives and chloroquine for efflux translocation sites, thus causing an increase in steady-state accumulation of chloroquine and a return to susceptibility. Restoration of therapeutic efficacy of chloroquine against resistant parasites by the administration of an additional drug available at relatively low cost may be a more effective strategy than the introduction of another antimalarial drug at the national level.

Synthesis and effects on chloroquine susceptibility in Plasmodium falciparum of a series of new dihydroanthracene derivatives.

To suggest a mechanism of action for drugs capable to reverse the chloroquine resistance, a new set of 9,10-dihydro-9,10-ethano and ethenoanthracene derivatives was synthesized and compounds were tested with the aim to assess their effect on chloroquine susceptibility in Plasmodium falciparum resistant strains. With respect to this, reversal of resistance and change in drug accumulation were compared. Structure-activity relationship and molecular modeling studies made it possible to define a pharmacophoric moiety for reversal agents and to propose a putative model of interaction with some selected amino acids.

In vitro increase in chloroquine accumulation induced by dihydroethano- and ethenoanthracene derivatives in Plasmodium falciparum-parasitized erythrocytes.

The effects of a series of dihydroethano- and ethenoanthracene derivatives on chloroquine (CQ) accumulation in CQ-susceptible strain 3D7 and CQ-resistant clone W2 were assessed. The levels of CQ accumulation increased little or none in CQ-susceptible strain 3D7 and generally increased markedly in CQ-resistant strain W2. At 10 microM, 28 compounds yielded cellular accumulation ratios (CARs) greater than that observed with CQ alone in W2. At 10 microM, in strain W2, 21 of 31 compounds had CQ CARs two or more times higher than that of CQ alone, 15 of 31 compounds had CQ CARs three or more times higher than that of CQ alone, 13 of 31 compounds had CQ CARs four or more times higher than that of CQ alone, and 9 of 31 compounds had CQ CARs five or more times higher than that of CQ alone. At 1 microM, 17 of 31 compounds had CQ CARs two or more times higher than that of CQ alone, 12 of 31 compounds had CQ CARs three or more times higher than that of CQ alone, 6 of 31 compounds had CQ CARs four or more times higher than that of CQ alone, and 3 of 31 compounds had CQ CARs five or more times higher than that of CQ alone. At 1 microM, 17 of 31 compounds were more potent inducers of CQ accumulation than verapamil and 12 of 31 compounds were more potent inducers of CQ accumulation than promethazine. The nature of the basic group seems to be associated with increases in the levels of CQ accumulation. At 1 and 10 microM, 10 of 14 and 13 of 14 compounds with amino group (amines and diamines), respectively, had CARs >or=3, while at 1 and 10 microM, only 1 of the 13 derivatives with amido groups had CARs >or=3. Among 12 of the 31 compounds which were more active inducers of CQ accumulation than promethazine at 1 microM, 10 had amino groups and 1 had an amido group.

Preparation of delta-Chloro-alpha-allenyl Ketones by Acylation of 3-Buten-1-ynes.

AlCl(3)-mediated acylation of 3-buten-1-yne derivatives with acyl chlorides yields a mixture of 5-chloro-2,3-pentadienones and 3-chloro-2,4-pentadienones. The proportion of allenyl ketones vs conjugated dienic ketones depends on the substitution pattern of the starting enyne. Acylation of 5-acetoxy-3-buten-1-ynes leads to the corresponding allenyl ketones (6-acetoxy-5-chloro-2,3-pentadienones).