Methyl 1,2,3,4,5,6-hexahydro-8-hydroxy-α,1,5,5-tetramethyl-γ-oxo-3a,6-ethano-3aH-indene-4-pentanoate

A series of camphecene and quinolizidine alkaloid (-)-cytisine conjugates has been obtained for the first time using 'click' chemistry methodology. The cytotoxicity and virus-inhibiting activity of compounds were determined against MDCK cells and influenza virus A/Puerto Rico/8/34 (H1N1), correspondingly, in in vitro tests. Based on the results obtained, values of 50 % cytotoxic dose (CC50 ), 50 % inhibition dose (IC50 ) and selectivity index (SI) were determined for each compound. It has been shown that the antiviral activity is affected by the length and nature of linkers between cytisine and camphor units. Conjugate 13 ((1R,5S)-3-(6-{4-[(2-{(E)-[(1R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene]amino}ethoxy)methyl]-1H-1,2,3-triazol-1-yl}hexyl)-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one), which contains cytisine fragment separated from triazole ring by -C6 H12 - aliphatic linker, showed the highest activity at relatively low toxicity (CC50 =168 μmol, IC50 =8 μmol, SI=20). Its selectivity index appeared higher than that of reference compound, rimantadine. According to theoretical calculations, the antiviral activity of the lead compound 13 can be explained by its influence on the functioning of neuraminidase.

Adiponectin, an adipokine with insulin-sensitizing effect, is secreted from adipocytes into circulation as high, medium, and low molecular weight forms (HMW, MMW, and LMW). The HMW adiponectin oligomers possess the most potent insulin-sensitizing activity. WSF-P-1(N-methyl-1,2,3,4,5,6-hexahydro-1,1,5,5-tetramethyl-7H-2,4α-methanonaphthalen-7-amine) is derived from natural sesquiterpene longifolene by chemical modifications. We found that WSF-P-1 activates AMPK in both 3T3-L1 adipocytes and 293T cells in this study. Activation of AMPK by WSF-P-1 promotes the assembly of HMW adiponectin and increases the HMW/total ratio of adiponectin in 3T3-L1 adipocytes. We demonstrated that the Ca2+-dependent CaMKK signaling pathway is involved in WSF-P-1-induced AMPK activation and adiponectin multimerization. WSF-P-1 also activates GLUT1-mediated glucose uptake in 3T3-L1 adipocytes, making it a potential drug candidate for the treatment of type 2 diabetes, obesity, and other obesity-related metabolic diseases.

Development of efficient sequences for the synthesis of the title compound (2-(2,2-dimethoxyethyl)-1,2,3,4,5,6-hexahydro-1,5-methanoazocino[4,3-b]indole) (7) was described. The title compound was synthesized through several steps starting from phenylhydrazine hydrochloride and dimethyl (R)-2-(3-oxocyclohexyl)malonate. In this route, all synthesized compounds were observed by spectroscopic tools (FT-IR, NMR): Methyl-2-(2,3,4,9-1H-carbazol-2-yl)acetate (3), 2-(2,3,4,9-tetrahydro-1H-carbazol-2-yl)acetic acid (4), N-(2,2-dimethoxyethyl)-2-(2,3,4,9-tetrahydro-1H-carbazol-2-yl)acetamide (5), 2-(2,2-dimethoxyethyl)-1,2,4,5,6,7-hexahydro-3H-1,5-methanoazocino[4,3-b]indol-3-one (6), 2-(2,2-dimethoxyethyl)-2,3,4,5,6,7-hexahydro-1H-1,5-methanoazocino[4,3-b]indole (7). The central step in these syntheses is the dehydrogenative reaction, which constructs the tetracyclic ring system from a much simpler tetracyclic precursor. The six-stable conformers of the compound (7) were used for further calculations such as FT-IR, NMR, NLO, and FMO analyses, performed at the B3LYP/6-311++G(d,p) level. This work revealed that (7) can be a good material to use in the non-linear optical material because its β tensor is greater ten times than that of the urea.