PLIN3 inhibitors (Maxim Pharmaceuticals)

Recent work on the diazonium ion metabolite of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNKDI) suggests that 5-(pyridin-3-yl)-3,4-dihydro-2 H -furan-1-ium (NNKFI) may form from NNKDI via an intramolecular reaction. NNKDI is an important carcinogen whose role as an alkylating agent has received significant attention. While there is some experimental evidence supporting NNKFI’s production in vitro , it has not yet been directly observed. Little is known about NNKFI’s structure and reactivity. We report the first in silico examination of this ion. Our study utilized Kohn–Sham density functional theory (B3LYP/6-311G**) and coupled cluster theory (CCSD/6-31G*) to produce energy-optimized structures, vibrational normal modes and molecular orbitals for NNKFI. To gain insight into the chemical properties of this species, we calculated electrostatic potential surfaces, natural population analysis charges and local Fukui indices. We report data and results for NNKFI’s cis and trans conformers. Our work confirms C5 as the preferred site for nucleophilic attack in NNKFI. Stretching motions and predicted bond lengths near O1 are consistent with a somewhat weakened carbonyl structure in this ion. Partial charges, electrostatic potential surfaces and local Fukui indices reveal delocalization of cationic charge on the furanium moiety and notable carbocation character at C5.

To get a deeper insight into the function of estrogen-related receptors (ERRs) and dissect underlying mechanism in Leydig cells, ERRs (type α, β and γ) were blocked or activated in testes of adult bank voles (Myodes glareolus) which show seasonal changes in the intratesticular sex hormones level. Both actively reproducing animals (long day conditions; LD) and those with regression of the reproductive system (short day conditions; SD) received intraperitoneal injections of selective ERRα antagonist 3-[4-(2,4-Bis-trifluoromethylbenzyloxy)-3-methoxyphenyl]-2-cyano-N-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)acrylamide (XCT 790) or selective ERRβ/ERRγ agonist N-(4-(Diethylaminobenzylidenyl)-N'-(4-hydroxybenzoyl)-hydrazine (DY131) (50 μ/kg bw; six doses every other day). Markedly more, XCT 790 (P < 0.05) but also DY131 affected interstitial tissue histology whose volume increased in both LD and SD males while seminiferous epithelium structure was untouched. Ultrastructure analysis revealed alterations in mitochondria number as well as endoplasmic reticulum and Golgi complexes volume and structure especially after ERRα blockage. Diverse and complex ERRs regulation at mRNA level and protein expression (P < 0.05; P < 0.01 and P < 0.001) of steroidogenic (lutropin receptor (LHR), translocator protein (TSPO), steroidogenic acute regulatory protein (StAR)) and secretory (insulin-like protein 3 (INSL3) and relaxin (RLN)) molecules were revealed in relations to endogenous estrogen level in treated males. Notably, immunolocalization of ERRs and above proteins, exclusively in Leydig cells, indicated their involvement in Leydig cell function control based on interactions with endogenous estrogen level and/or estrogen signaling via ERRs. Treatment with XCT 790 or DY131 significantly decreased (P < 0.05; P < 0.01 and P < 0.001) intratesticular estrogens concentration, with exception in SD DY131 males. In addition, androgens level was decreased, but not in LD DY131 voles. Similarly, ERRβγ activation significantly reduced (P < 0.05; P < 0.01 and P < 0.001) cAMP and calcium ions (Ca²⁺) concentrations particularly in DY131 voles. Overall, for the first time, we have shown that ERRs are involved in maintenance of Leydig cell architecture and supervision of its steroidogenic and secretory activity that is closely related to endogenous estrogen status in the testis. Further understanding of mechanism(s) by which individual types of ERRs can control Leydig cell function is relevant for predicting and preventing steroidogenic and spermatogenic disorders.