Biophysical Evaluation and In Vitro Controlled Release of Two Isomeric Adamantane Phenylalkylamines with Antiproliferative/Anticancer and Analgesic Activity.

The aqueous dissolution profile of the isomeric synthetic adamantane phenylalkylamine hydrochlorides I and II was probed. These adducts have shown significant antiproliferative/anticancer activity associated with an analgesic profile against neuropathic pain. They are both devoid of toxic effects and show appreciable enzymatic human plasma stability. The structures of these two compounds have been elucidated using 2D NMR experiments, which were used to study their predominant conformations. Compound II's scaffold appeared more flexible, as shown by the NOE spatial interactions between the alkyl bridge chain, the aromatic rings, and the adamantane nucleus. Conversely, compound I appeared very rigid, as it did not share significant NOEs between the aforementioned structural segments. MD simulations confirmed the NOE results. The aqueous dissolution profile of both molecules fits well with their minimum energy conformers' features, which stem from the NOE data; this was nicely demonstrated, especially in the case of compound II.

Synthesis and in vitro Biological Evaluation of Novel Thymidine Analogs Containing 1H-1,2,3-Triazolyl, 1H-Tetrazolyl, and 2H-Tetrazolyl Fragments.

3'-Azidothymidine (AZT) reacts with 1-propargyl-5-R-1H- and 2-propargyl-5-R-2H-tetrazoles (R = H, Me, CH2COOEt, CH2CON(CH3)2, Ph, 2-CH3-C6H4, or 4-NO2-C6H4) via the Cu(I)-catalyzed asymmetric [3 + 2] cycloaddition to give 3'-modified thymidine analogs incorporating 1H-1,2,3-triazolyl, 1H-, and 2H-tetrazolyl fragments in 41-76% yield. The structures of the obtained compounds have been elucidated by means of HRESI+-MS, 1H and 13 C{1H} NMR, and single crystal X-ray diffraction {for 3'-[4-(1H-5-N,N-dimethylaminocarbonylmethyltetrazol-1-yl)-1H-1,2,3-triazol-1-yl]thymidine 10d}. In vitro biological evaluation of the prepared compounds has been performed; they have exhibited low activity against phenotypic HIV-1899A. Moderate anti-influenza activity against influenza virus A/Puerto Rico/8/34 (H1N1) strain has been observed in the cases of 3'-(4-(1H-tetrazol-1-ylmethyl)-1H-1,2,3-triazol-1-yl)thymidine 10a (IC50 39.6 µg/mL), 3'-(4-(2H-5-ethoxycarbonyltetrazol-2-ylmethyl)-1H-1,2,3-triazol-1-yl)thymidine 11c (IC50 31.6 µg/mL), and 3'-(4-(2H-5-(4-nitrophenyl)-tetrazol-2-ylmethyl)-1H-1,2,3-triazol-1-yl)thymidine 11g (IC50 46.4 µg/mL). The tested compounds possess very low cytotoxicity towards MDCK and MT4 cells as well as tumor human cervical carcinoma HeLa and promyelocytic leukemia HL-60 cells.

Bufadienolides from parotoid gland secretions of Cuban toad Peltophryne fustiger (Bufonidae): Inhibition of human kidney Na(+)/K(+)-ATPase activity.

Parotoid gland secretions of toad species are a vast reservoir of bioactive molecules with a wide range of biological properties. Herein, for the first time, it is described the isolation by preparative reversed-phase HPLC and the structure elucidation by NMR spectroscopy and/or mass spectrometry of nine major bufadienolides from parotoid gland secretions of the Cuban endemic toad Peltophryne fustiger: ψ-bufarenogin, gamabufotalin, bufarenogin, arenobufagin, 3-(N-suberoylargininyl) marinobufagin, bufotalinin, telocinobufagin, marinobufagin and bufalin. In addition, the secretion was analyzed by UPLC-MS/MS which also allowed the identification of azelayl arginine. The effect of arenobufagin, bufalin and ψ-bufarenogin on Na(+)/K(+)-ATPase activity in a human kidney preparation was evaluated. These bufadienolides fully inhibited the Na(+)/K(+)-ATPase in a concentration-dependent manner, although arenobufagin (IC50 = 28.3 nM) and bufalin (IC50 = 28.7 nM) were 100 times more potent than ψ-bufarenogin (IC50 = 3020 nM). These results provided evidence about the importance of the hydroxylation at position C-14 in the bufadienolide skeleton for the inhibitory activity on the Na(+)/K(+)-ATPase.