876-05-1Relevant articles and documents
Synthesis, antiproliferative activity in cancer cells and DNA interaction studies of [Pt(cis-1,3-diaminocycloalkane)Cl2] analogs
Hoeschele, James D.,Kasparkova, Jana,Kostrhunova, Hana,Novakova, Olga,Pracharova, Jitka,Pineau, Paul,Brabec, Viktor
, p. 913 - 924 (2020/09/01)
Abstract: The search for more effective platinum anticancer drugs has led to the design, synthesis, and preclinical testing of hundreds of new platinum complexes. This search resulted in the recognition and subsequent FDA approval of the third-generation Pt(II) anticancer drug, [Pt(1,2-diaminocyclohexane)(oxalate)], oxaliplatin, as an effective agent in treating colorectal and gastrointestinal cancers. Another promising example of the class of anticancer platinum(II) complexes incorporating the Pt(1,n-diaminocycloalkane) moiety is kiteplatin ([Pt(cis-1,4-DACH)Cl2], DACH = diaminocyclohexane). We report here our progress in evaluating the role of the cycloalkyl moiety in these complexes focusing on the synthesis, characterization, evaluation of the antiproliferative activity in tumor cells and studies of the mechanism of action of new [Pt(cis-1,3-diaminocycloalkane)Cl2] complexes wherein the cis-1,3-diaminocycloalkane group contains the cyclobutyl, cyclopentyl, and cyclohexyl moieties. We demonstrate that [Pt(cis-1,3-DACH)Cl2] destroys cancer cells with greater efficacy than the other two investigated 1,3-diamminocycloalkane derivatives, or cisplatin. Moreover, the investigated [Pt(cis-1,3-diaminocycloalkane)Cl2] complexes show selectivity toward tumor cells relative to non-tumorigenic normal cells. We also performed several mechanistic studies in cell-free media focused on understanding some early steps in the mechanism of antitumor activity of bifunctional platinum(II) complexes. Our data indicate that reactivities of the investigated [Pt(cis-1,3-diaminocycloalkane)Cl2] complexes and cisplatin with glutathione and DNA binding do not correlate with antiproliferative activity of these platinum(II) complexes in cancer cells. In contrast, we show that the higher antiproliferative activity in cancer cells of [Pt(cis-1,3-DACH)Cl2] originates from its highest hydrophobicity and most efficient cellular uptake. Graphic abstract: [Figure not available: see fulltext.]
Conformational Restriction and Enantioseparation Increase Potency and Selectivity of Cyanoguanidine-Type Histamine H4 Receptor Agonists
Geyer, Roland,Nordemann, Uwe,Strasser, Andrea,Wittmann, Hans-Joachim,Buschauer, Armin
supporting information, p. 3452 - 3470 (2016/05/19)
2-Cyano-1-[4-(1H-imidazol-4-yl)butyl]-3-[2-(phenylsulfanyl)ethyl]guanidine (UR-PI376, 1) is a potent and selective agonist of the human histamine H4 receptor (hH4R). To gain information on the active conformation, we synthesized analogues of 1 with a cyclopentane-1,3-diyl linker. Affinities and functional activities were determined at recombinant hHxR (x: 1-4) subtypes on Sf9 cell membranes (radioligand binding, [35S]GTPγS, or GTPase assays) and in part in luciferase assays on human or mouse H4R (HEK-293 cells). The most potent H4R agonists among 14 racemates were separated by chiral HPLC, yielding eight enantiomerically pure compounds. Configurations were assigned based on X-ray structures of intermediates and a stereocontrolled synthetic pathway. (+)-2-Cyano-1-{[trans-(1S,3S)-3-(1H-imidazol-4-yl)cyclopentyl]methyl}-3-[2-(phenylsulfanyl)ethyl]guanidine ((1S,3S)-UR-RG98, 39a) was the most potent H4R agonist in this series (EC50 11 nM; H4R vs H3R, >100-fold selectivity; H1R, H2R, negligible activities), whereas the optical antipode proved to be an H4R antagonist ([35S]GTPγS assay). MD simulations confirmed differential stabilization of the active and inactive H4R state by the enantiomers.
Tetrapropylammonium perruthenate catalyzed glycol cleavage to carboxylic (Di)acids
Schmidt, Andrea-Katharina C.,Stark, Christian B. W.
supporting information; experimental part, p. 5788 - 5791 (2011/12/05)
A new method to accomplish glycol cleavage to carboxylic (di)acids in one step using catalytic amounts of tetrapropylammonium perruthenate (TPAP) together with N-methylmorpholine N-Oxide (NMO) as the stoichiometric oxidant is presented. In addition to regenerating the active catalyst, the N-oxide stabilizes intermediary carbonyl hydrates and thereby shifts a crucial equilibrium. The mild oxidation protocol is applicable to a broad range of substrates providing the respective acids, diacids, or keto acids in high yields.
