The synthesis of novel 7-(4-halophenyl)-8,9-dihydro-7H-12-oxa-9,11-diaza-benzo[a]anthracene derivatives has been reported. The key intermediate 3-amino-9-chloro-1-(4-halophenyl)-1H-benzo[h]chromene-2-carbonitrile (3) was obtained by treating 4-halobenzylidenmalononitriles (1a-c) and ethyl 4-halobenzylidenmalonates (1d-f) with 4-chloro-1-naphthol (2) in ethanolic piperidine solution. Antimicrobial activity was shown for most of the synthesized compounds.

Synthesis of halogen derivatives of benzo[h]chromene and benzo[a]anthracene with promising antimicrobial activities.

Natural and synthetic chromenes, fused chromenes, and versatility of dihydrobenzo[h]chromenes in organic synthesis.

Aqua mediated synthesis of substituted 2-amino-4H-chromenes and in vitro study as antibacterial agents.

DBU: a highly efficient catalyst for one-pot synthesis of substituted 3,4-dihydropyrano[3,2-c]chromenes, dihydropyrano[4,3-b]pyranes, 2-amino-4H-benzo[h]chromenes and 2-amino-4H benzo[g]chromenes in aqueous medium

Organic synthesis performed through multicomponent reactions is an attractive area of research in organic chemistry. Multicomponent reactions involve more than two starting reagents that couple in an exclusive ordered mode under the same reaction conditions to form a single product which contains the essential parts of the starting materials. Multicomponent reactions are powerful tools in modern drug discovery processes, because they are an important source of molecular diversity, allowing rapid, automated and high throughput generation of organic compounds. This review aims to illustrate progress in a large variety of catalyzed multicomponent reactions performed with acid, base and metal heterogeneous and homogeneous catalysts. Within each type of multicomponent approach, relevant products that can be obtained and their interest for industrial applications are presented.

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Homogeneous and heterogeneous catalysts for multicomponent reactions

Summary Pyran (divinyl ether-maleic anhydride) copolymer (NSC 46015) is a polyanion with interferon-inducing and macrophage-stimulating properties, and therefore it has been studied as a possible antitumor agent. Extensive studies using pyran as an adjuvant to chemotherapy against the LSTRA murine leukemia and the Lewis lung carcinoma were performed. Pyran was effective over a dose range of 0.1 to 100 mg/kg/day. Single and multiple dose schedules were both capable of producing significant numbers of cures or increasing life-span, but pyran was ineffective if used without remission inducing chemotherapy. Various molecular weights of pyran copolymer were compared against NSC 46015 for adjuvant activity as well. In general, NSC 46015 tended to be the most efficacious, but all the pyran sizes that were tested possessed significant activity.

https://cancerres.aacrjournals.org/content/canres/35/12/3750.full.pdf

Pyran Copolymer as an Effective Adjuvant to Chemotherapy against a Murine Leukemia and Solid Tumor

Summary The immune response of BALB/c × DBA/2 F1 mice to a transplantable Moloney leukemia virus-induced tumor allograft (MBL-2) was studied to determine the mechanism of pyran copolymer-induced tumor enhancement. The relative levels of humoral, lymphocyte, and macrophage response were followed chronologically by in vitro cytotoxic microassays using 51Cr-labeled target cells. Although pyran increased the titer of humoral cytotoxic antibody, levels of humoral factors capable of abrogating lymphocytoxicity were not enhanced. Furthermore, splenic lymphocyte-mediated cytotoxicity, although slightly diminished in pyrantreated mice, was not significantly affected. Macrophages harvested from allograft-bearing animals exhibited marked tumoricidal activity, which was augmented by pyran treatment. This macrophage-associated activity was specific for MBL-2 cells and not attributable to cytotoxins elaborated into the culture medium. Pyran slightly activated macrophages from nonsensitized mice to become cytotoxic for MBL-2 cells; activation was not T-cell dependent. However, strikingly fewer macrophages infiltrated the allograft in pyran-treated animals as judged by both histopathology and direct measurement. The defect in the migration or deposit of macrophages at the allograft site may have contributed to tumor enhancement.

Immune response of BALB/c X DBA/2F1 mice to a tumor allograft during pyran copolymer-induced tumor enhancement.

Pyran copolymer (NSC 46015) was found to potentiate strongly the immune response of C57BL/6J X DBA/2 F1 mice to 10(4) live L1210 tumor cells following suboptimal vaccination with 10(7) radiation-inactivated L1210 cells. Optimal immunity to challenge was produced by concomitant i.p administration of pyran and L1210 vaccine, and activity was dependent upon both pyran and vaccine dosages. In addition, this immunopotentiation seemed to be related to the intrinsic viscosity of different pyran preparations tested, although all the pyran compounds had significant activity. Furthermore, the increased immunity of subsequent live tumor challenge appeared to be specific for the vaccinating cell type.

https://cancerres.aacrjournals.org/content/canres/36/6/2035.full.pdf

Specific potentiation of L1210 vaccine by pyran copolymer.

Pyran copolymer (NSC 46015) was evaluated with respect to its effect on the rejection of a murine leukemic allograft by BALB/c x DBA/2 F1 (CD2F1) mice. Significant prolongation of allograft survival with production of progressively growing lethal tumors was found following pyran administration. This phenomenon occurred at nontoxic doses of the drug and appeared to be closely related to the timing of pyran injection. Nonspecifically stimulated lymphocyte blast transformation by concanavalin A was not impaired by pyran when lymphocytes were exposed in vitro to the drug. The mechanism of tumor allograft enhancement remains obscure but may be related to allograft size at the time of pyran administration.

https://cancerres.aacrjournals.org/content/canres/36/4/1315.full.pdf

Enhancement of a tumor allograft in BALB/c x DBA/2 F1 mice by pyran copolymer.

Pyran copolymer (NSC 46015) is a polyanionic compound of varying molecular weight and is a well-known interferon inducer. Recently, pyran has received considerable attention because of its strong macrophage-activating and immunopotentiating properties and their application in various oncological systems. The mechanism(s) of action for these various biological phenomena remains unknown. We herein report that pyran is capable of interacting with the repressed genome of isolated murine liver nuclei in such a way as to allow DNA synthesis to take place, when assayed with exogenous bacterial DNA polymerase. This interaction occurred immediately and was influenced by the magnesium concentration, pyran concentration, and molecular weight of the pyran. Furthermore, pyran could reverse the histone-induced inhibition of a pure poly(deoxyadenylate-deoxythymidylate) template primer for DNA synthesis. None of these observations was due to interaction of pyran with the nuclear membrane, because parallel results were obtained whether intact nuclei or nuclei that had undergone membrane disruption were used. In addition, morphological swelling of the nuclei was seen when in the presence of pyran concentrations that were maximally stimulatory to DNA synthesis. Pyran, therefore, is able to release the DNA template of murine liver nuclei from restrictions that normally would prevent them from serving as a useful template for DNA synthesis. It remains unclear whether these observations are directly relevant to the mechanisms of action that explain the broad biological activity of pyran, but the phenomenon is one that should not be overlooked.

https://cancerres.aacrjournals.org/content/canres/38/6/1610.full.pdf

Stephen J. Mohr

Papers

Pyran Copolymer as an Effective Adjuvant to Chemotherapy against a Murine Leukemia and Solid Tumor

Immune response of BALB/c X DBA/2F1 mice to a tumor allograft during pyran copolymer-induced tumor enhancement.

Specific potentiation of L1210 vaccine by pyran copolymer.

Enhancement of a tumor allograft in BALB/c x DBA/2 F1 mice by pyran copolymer.

Drepression of nuclear template restrictions for DNA synthesis by the immunostimulator pyran copolymer.