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M J Haddadin

Publications and source records attributed to M J Haddadin.

7 recordsLinked to original sources
PubMed2001

Novel CFTR chloride channel activators identified by screening of combinatorial libraries based on flavone and benzoquinolizinium lead compounds.

The flavonoid genistein and the benzo[c]quinolizinium MPB-07 have been shown to activate the cystic fibrosis transmembrane conductance regulator (CFTR), the protein that is defective in cystic fibrosis. Lead-based combinatorial and parallel synthesis yielded 223 flavonoid, quinolizinium, and related heterocyclic compounds. The compounds were screened for their ability to activate CFTR at 50 microm concentration by measurement of the kinetics of iodide influx in Fisher rat thyroid cells expressing wild-type or G551D CFTR together with the green fluorescent protein-based halide indicator YFP-H148Q. Duplicate screenings revealed that 204 compounds did not significantly affect CFTR function. Compounds of the 7,8-benzoflavone class, which are structurally intermediate between flavones and benzo[c]quinoliziniums, were effective CFTR activators with the most potent being 2-(4-pyridinium)benzo[h]4H-chromen-4-one bisulfate (UCcf-029). Compounds of the novel structural class of fused pyrazolo heterocycles were also strong CFTR activators with the most potent being 3-(3-butynyl)-5-methoxy-1-phenylpyrazole-4-carbaldehyde (UCcf-180). A CFTR inhibitor was also identified. The active compounds did not induce iodide influx in null cells deficient in CFTR. Short-circuit current measurements showed that the CFTR activators identified by screening induced strong anion currents in the transfected cell monolayers grown on porous supports. Compared with genistein, the most active compounds had up to 10 times greater potency in activating wild-type and/or G551D-CFTR. The activators had low cellular toxicity and did not elevate cellular cAMP concentration or inhibit phosphatase activity, suggesting that CFTR activation may involve a direct interaction. These results establish an efficient screening procedure to identify CFTR activators and inhibitors and have identified 7,8-benzoflavones and pyrazolo derivatives as novel classes of CFTR activators.

Animals↗
PubMed2001

Synthesis and reactions of some heterocyclic azacyanines.

The one-step reaction of some amino-substituted heterocycles with diiodomethane to give azacyanines is reported. This useful reaction is of wider application than initially reported and includes the synthesis of new substituted pyrido-, isoquino-, benzimadazo-, and benzothiazoazacyanines 7. Furthermore, treatment of these azacyanines with base generally affects a facile opening of the dihydrotriazinium ring resulting in the formation of new heterocycles 10, 11, and 12, which would be difficult to prepare by other means. This reaction takes an additional direction in the case of halo-substituted azacyanines 7b/c/d where treatment with base gives rise to new interesting derivatives of dipyridotriazines 14b/c/d.

Journal Article↗
PubMed1998

Photoprotective effects of some quinoxaline 1,4-dioxides in hairless mice.

2-benzoyl-3-phenylquinoxaline 1,4-dioxide (BPQ) and other substituted quinoxaline 1,4-dioxides (QdO) were tested for their ability to inhibit the stimulations of ornithine decarboxylase (ODC) enzyme activity and DNA synthesis, two biochemical markers linked to skin tumour promotion by ultraviolet B (UVB) radiation. Topical application of BPQ on the dorsal skin of hairless mice was found to inhibit in a dose-dependent manner UVB-induced ODC activity and DNA synthesis. When applied 20 min before UVB radiation, a dose of 17 mg BPQ applied in 0.4 ml of vehicle inhibited UVB-induced ODC activity and DNA synthesis by 95% and 85%, respectively. This inhibitory effect is dependent on the time of administration of BPQ relative to UVB radiation, with a generally greater inhibition observed when this compound is applied before rather than after UVB treatment. The inhibitory abilities of the other QdO on the ODC and DNA responses induced by UVB radiation greatly varied and appear to be dependent on the structure of the compounds and their metabolic activation in the skin following irradiation. The remarkable effectiveness of BPQ against the ODC and DNA markers of UVB promotion is also observed following multiple applications of this agent. These results suggest that QdO, in particular BPQ and certain derivatives of it, may be useful in protecting the skin against UVB-induced skin damage.

Animals↗
PubMed1975

Solvolytic reactions of cyclic anhydrides in anhydrous acetic acid.

The reversible reactions of several cyclic anhydrides with acetic acid to form acetic anhydride and the corresponding dicarboxylic acid, catalyzed by perchloric acid at 25degree, were studied. The equilibrium constants, calculated from spectral data, were 4.85 X 10-4, 1.08 X 10-1, and 4.6 X 10-1 M for succinic, trans-1,2-cyclohexanedicarboxylic, and glutaric anhydrides, respectively. Maleic, phthalic, and cis-1,2-cyclohexanedicarboxylic anhydrides did not undergo any detectable reaction with acetic acid under these conditions, suggesting still higher stability. The reverse rate constants were found to be relatively independent of the structure of the attacking diacid, while the forward rate constants were found to parrallel the equilibrium constants. The rate-determining step for the forward reaction appears to be the breakdown of the tetrahedral intermediate formed by the attack of an acetic acid molecule on the protonated cyclic anhydride.

Acetates↗
PubMed1975

Acylation of phenol by cyclic and acyclic anhydrides in anhydrous acetic acid.

Acylation of phenol with succinic, glutaric, trans-1,2-cyclohexanedicarboxylic, maleic, phthalic, and cis-1,2-cyclohexanedicarboxylic anhydrides in anhydrous acetic acid generally resulted in phenyl acetate as the major product. The formation of phenyl acetate as the major reaction product could be rationalized as being due to the reactivity of the cyclic anhydrides with acetic acid to form acetic anhydride as well as the greater reactivity of phenol with formed acetic anhydride than with the cyclic anhydride.

Acetates↗
PubMedDate not supplied

Quinoxaline 1,4-dioxides as anticancer and hypoxia-selective drugs.

Hypoxic cells which are found in solid tumors are resistant to anticancer drugs and radiation therapy. Thus, for effective anticancer chemotherapy, it is important to identify drugs with selective toxicity towards hypoxic cells. Quinoxaline 1,4-dioxides (QdNOs) are heterocyclic aromatic N-oxides that have been found to possess potent antibacterial activities (inhibit microbial DNA synthesis) especially under anaerobic conditions; thus they are under evaluation as bioreductive drugs for the treatment of solid tumors (1). We investigated the ability of four differently substituted QdNOs to inhibit cell growth and induce cell cycle changes in two human tumorigenic epithelial cell lines under oxic conditions. We also evaluated the toxicity of these drugs to cancer cells cultured under hypoxic conditions. Two epithelial cell lines (the T-84 human colon cancer-derived cell line, and the SP-1 keratinocyte cell line) were treated with various doses of the QdNOs and harvested at different times after treatment. Proliferation and cell cycle results showed a structure-function relationship in the activity of the various QdNO compounds with the 2-benzoyl-3-phenyl-6,7-dichloro-derivative of QdNO (DCBPQ) being the most potent cytotoxin and hypoxia-selective drug. The 2-benzoyl-3-phenyl (BPQ) and the 2-acyl-3-methyl-derivative of QdNO (AMQ) were less cytotoxic but arrested almost 50% of the cells in the G2M phase of the cell cycle at doses of 30 and 120 microM, respectively. The tetramethylene derivative of QdNO (TMQ) did not affect the growth and cycling of cells cultured in air and was the least potent cytotoxin to hypoxic cells. Our results indicate that the QdNOs are hypoxia-cytotoxic drugs whose activity varies according to the substituents on the quinoxaline 1,4-dioxide heterocycle. Because of their selective toxicity to hypoxic cells (cells found in human tumors), these drugs may provide useful therapeutic agents against solid tumors.

Antineoplastic Agents↗