Synthesis and Pharmacological Characterization of a Difluorinated Analogue of Reduced Haloperidol as a Sigma-1 Receptor Ligand.
作者: Run-Duo Gao ; Michelle Taylor ; Tamara McInnis ; Zhenglan Chen ; Sadakatali S Gori ; Heather M LaPorte ; Maxime A Siegler ; Janet L Neisewander ; Robert H Mach ; Meharvan Singh ; Barbara S Slusher ; Rana Rais ; Robert R Luedtke ; Takashi Tsukamoto
Reduced haloperidol (1) was previously reported to act as a potent sigma-1 receptor (S1R) ligand with substantially lower affinity to the dopamine D2 receptor (D2R) compared to haloperidol. It was also found to facilitate brain-derived neurotrophic factor (BDNF) secretion from astrocytic glial cell lines in a sigma-1 receptor (S1R)-dependent manner. Although an increase in BDNF secretion may have beneficial effects in some neurological conditions, the therapeutic utility of reduced haloperidol (1) is limited because it can be oxidized back to haloperidol in the body, a potent dopamine D2 receptor antagonist associated with well-documented adverse effects. A difluorinated analogue of reduced haloperidol, (±)-4-(4-chlorophenyl)-1-(3,3-difluoro-4-(4-fluorophenyl)-4-hydroxybutyl)piperidin-4-ol (2), was synthesized in an attempt to minimize the oxidation. Compound (±)-2 was found to exhibit high affinity to S1R and facilitate BDNF release from mouse brain astrocytes. It was also confirmed that compound 2 cannot be oxidized back to the corresponding haloperidol analogue in liver microsomes. Furthermore, compound 2 was distributed to the brain following intraperitoneal administration in mice and reversed the learning deficits in active avoidance tasks. These findings suggest that compound 2 could serve as a promising S1R ligand with therapeutic potential for the treatment of cognitive impairments.
2023-01-22·Molecules (Basel, Switzerland)
Synthesis, Characterization, and Antiproliferative Properties of New Bio-Inspired Xanthylium Derivatives.
作者: Claudia Koch ; Diana-Maria Dreavă ; Anamaria Todea ; Francisc Péter ; Mihai Medeleanu ; Iulia Păușescu ; Corina Samoilă ; Ioan Ovidiu Sîrbu
Xanthylium derivatives are curcumin analogs showing photochromic properties. Similarly, to anthocyanins, they follow the same multistate network of chemical species that are reversibly interconverted by external stimuli. In the present work, two new asymmetric monocarbonyl analogues of curcumin, 4-(4-hydroxy-3-metoxybenzylidene)-1,2,3,4-tetrahydroxanthylium chloride (compound 3) and 4-(4-hydroxybenzylidene)-6-methoxy-1,2,3,4-tetrahydroxanthylium chloride (compound 4) were synthesized, and their photochromic and biological properties were investigated. The UV-Vis spectroscopy and the direct and reverse pH-jumps studies confirmed the halochromic properties and the existence of different molecular species. A network of chemical reactions of these species was proposed. Furthermore, the antiproliferative properties of both compounds were evaluated using P19 murine embryocarcinoma cells and compared with each other. The results demonstrate that both new xanthylium derivatives modify the progression through the cell cycle of P19 cells, which translates into a significant antiproliferative effect. The effect of the methoxy group position is discussed and several checkpoint proteins are advanced as putative targets.
2023-01-05·Bulletin of experimental biology and medicine
Cytostatic Activity of Combretastatin A-4 Derivatives in an In Vitro System.
作者: A D Plyutinskaya ; E R Nemtsova ; A A Pankratov ; P V Shegai ; S S Krylov ; V N Iskandarova ; A S Maksimenko ; D V Demchuk ; T S Kuptsova ; M N Semenova ; V V Semenov
Cytostatic activity of combretastatin A-4, its 11 analogues, and paclitaxel (Taxacad) was evaluated in vitro on human tumor cells A549 (lung adenocarcinoma) and PC-3 (prostate adenocarcinoma) in order to find the active and stable compound as a promising antitumor agent. 5-(4-Methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-isoxazole (compound 123124) and 3-(3,4,5-trimethoxyphenyl)-4-(4-methoxyphenyl)-isoxazole (compound 29310186) demonstrated the highest cytostatic activity (IC50≈8×10-9 М). The activity of two other cytotoxic compounds (2E)-1-(7-methoxy-2H-1,3-benzodioxol-5-yl)-3-(4-methoxyphenyl)prop-2-en-1-one (compound 104815) and 4-(3-amino-4-methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-1H-pyrazole hydrochloride (compound 198732) was close to that of Taxacad: IC50 65×10-9 and 80×10-9 М, respectively, and are also promising active components for the development of antitumor drugs.