Structure-Activity Relationship and Bioactivity Studies of Neurotrophic trans-Banglene

Neurotrophic small molecule natural products are functional analogs of signaling proteins called neurotrophins, which cause a pro-growth, pro-survival, or pro-differentiation response in neuronal cells. While these phenotypic responses are desirable to combat neurodegenerative disease progression, the pharmacokinetic properties of neurotrophins present challenges to their administration. Therefore, neurotrophic small molecules such as the cis- and trans-banglenes offer attractive alternatives. We describe the synthesis and testing of banglene derivatives and establish a structure-activity response for the banglene family. We demonstrate that (–) trans-banglene is the primarily active enantiomer, and that select modifications on the cyclohexene ring of trans-banglene do not significantly impair its bioactivity. Finally, we demonstrate that (–) trans-banglene potentiation of NGF induced neuritogenesis is unaffected by the presence of these Erk1/2, Akt and Pkc inhibitors. Our structure-activity results also suggest that (–) trans-banglene neurotrophic activity and its potentiation of NGF activity might be distinct unassociated processes.

Structure-Activity-Relationship and Bioactivity of Neurotrophic trans-Banglene

Neurotrophic small molecule natural products are functional analogs of signaling proteins called neurotrophins, which cause a pro-growth, pro-survival, or pro-differentiation response in neuronal cells. While these phenotypic responses are desirable to combat neurodegenerative disease progression, the pharmacokinetic properties of neurotrophins present challenges to their administration. Therefore, neurotrophic small molecules such as the cis- and trans-banglenes offer attractive alternatives. We describe the synthesis and testing of banglene derivatives and establish a structure-activity response for the banglene family. We demonstrate that (–) trans-banglene is the primarily active enantiomer, and that select modifications on the cyclohexene ring of trans-banglene do not significantly impair its bioactivity. Finally, we demonstrate that (–) trans-banglene potentiation of NGF induced neuritogenesis is unaffected by the presence of these Erk1/2, Akt and Pkc inhibitors. Our structure-activity results also suggest that (–) trans-banglene neurotrophic activity and its potentiation of NGF activity might be distinct unassociated processes.

Structure-Activity-Relationship and Bioactivity of Neurotrophic trans-Banglene

Neurotrophic small molecule natural products are functional analogs of signaling proteins called neurotrophins, which cause a pro-growth, pro-survival, or pro-differentiation response in neuronal cells. While these phenotypic responses are desirable to combat neurodegenerative disease progression, neurotrophin proteins possess pharmacokinetic properties that present challenges to their administration in living organisms, whether in biomedical studies or as therapeutics. Small molecules such as the cis- and trans-banglenes offer attractive alternatives to activate neurotrophic responses. We describe the synthesis and testing of banglene derivatives to establish a structure-activity response for the banglene family. Notably, during the course of our studies trans-banglene was shown to cause nerve growth factor (NGF)-potentiated neuritogenesis that was markedly stronger than the neuritogenic effects of trans-banglene alone. We demonstrate that only (–) trans-banglene is active, while its (+) enantiomer is not, and further demonstrate that select modifications on the cyclohexene ring of trans-banglene does not impair its bioactivity. Finally, to probe the relationship between (–) trans-banglene’s mechanism of ac-tion and canonical NGF signal transduction pathways, we employed kinase inhibitors targeting Pkc, Akt1/2/3 and Erk1/2, designed to inhibit NGF-induced neurotrophic signaling. Interestingly, (–) trans-banglene potentiation of NGF-induced neuri-togenesis was unaffected by the presence of these kinase inhibitors. Collectively, these results suggest a dual-mode of action for (–) trans-banglene (both neurotrophic alone and strongly potentiating of NGF activity), and an independence of its po-tentiating action on Pkc and Erk1/2 enzymatic activity.

Crystal structure and Hirshfeld surface analysis of 2-{[7-acetyl-8-(4-chlorophenyl)-4-cyano-6-hydroxy-1,6-dimethyl-5,6,7,8-tetrahydroisoquinolin-3-yl]sulfanyl}-N-(4-chlorophenyl)acetamide

In the title molecule, C28H25Cl2N3O3S, the heterocyclic portion of the tetrahydroisoquinoline unit is planar while the cyclohexene ring adopts a twist-boat conformation. The two 4-chlorophenyl groups extend away from one side of this unit while the hydroxyl and acetyl groups extend away from the opposite side and form an intramolecular O—H...O hydrogen bond. The crystal packing consists of layers parallel to the bc plane. A Hirshfeld surface analysis of the crystal structure indicates that the most important contributions to the crystal packing are from H...H (37.3%), Cl...H/H...Cl (17.6%), O...H/H...O (11.1%), C...H/H...C (10.9%) and N...H/H...N (9.7%) interactions.

Crystal structures of 1-(4-chlorophenyl)-4-(4-methylphenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxylic acid and 4-(4-methoxyphenyl)-1-(4-methylphenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonitrile

In the title compounds C23H21ClN2O3 [I, namely 1-(4-chlorophenyl)-4-(4-methylphenyl)-3,8-dioxo-1,2,5,6,7,8-hexahydroquine-3-carboxylic acid] and C24H22N2O3 [II, namely 4-(4-methoxyphenyl)-1-(4-methylphenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonitrile], each of the cyclohexene and dihydropyridine rings of the 1,2,5,6,7,8-hexahydroquinoline moieties adopts a twisted-boat conformation. The asymmetric units of both compounds I and II consist of two independent molecules (A and B). In II A, three carbon atoms of the cyclohexene ring are disordered over two sets of sites in a 0.670 (11):0.330 (11) occupancy ratio. In the crystal of I, molecules are linked through classical N—H...O hydrogen bonds, forming inversion dimers with an R 2 2(8) ring motif and with their molecular planes parallel to the crystallographic (020) plane. Non-classical C—H...O hydrogen-bonding interactions connect the dimers, resulting in a three-dimensional network. In the crystal of II, molecules are linked by C—H...N, C—H...O and C—H...π interactions, forming a three-dimensional network.

Crystal structure of (4bS,8aR)-1-isopropyl-4b,8,8-trimethyl-7-oxo-4b,7,8,8a,9,10-hexahydrophenanthren-2-yl acetate

The title compound, C22H28O3, was prepared by a direct acetylation reaction of naturally occurring totarolenone. The molecule contains three fused rings, which exhibit different conformations. The central ring has a half-chair conformation, while the non-aromatic oxo-substituted ring has a screw-boat conformation. In the crystal, molecules are linked by C—H...O hydrogen bonds and C—H...π interactions, forming sheets parallel to the bc plane. The carbonyl O atoms and the C atom at the 6-position of the cyclohexene ring are each disordered over two sets of sites with major occupancy components of 0.63 (7) and 0.793 (14), respectively.

Influence of structure of lactones with the methylcyclohexene and dimethylcyclohexene ring on their biotransformation and antimicrobial activity

The aim of this article is influence of the structure of lactones with the methylcyclohexene and dimethylcyclohexene ring on their biotransformation and antimicrobial activity. This work was based on the general remark that even the smallest change in the structure of a compound can affect its biological properties. The results of the biotransformation of four bicyclic unsaturated lactones with one or two methyl groups in the cyclohexene ring was tested using fifteen fungal strains (Fusarium species, Penicillium species, Absidia species, Cunninghamella japonica, and Pleurotus ostreatus) and five yeast strains (Yarrowia lipolytica, Rhodorula marina, Rhodorula rubra, Candida viswanathii, and Saccharomyces cerevisiae). During these transformations, new epoxylactone and hydroxylactone were obtained. The relationship between the substrate structure and the ability of the microorganisms to transform them were analysed. Only compounds with C–O bond of lactone ring in the equatorial position were transformed by fungus. All presented here lactones were examined also for their antimicrobial activity. It turned out that these compounds exhibited growth inhibition of bacteria and fungi, mainly Bacillus subtilis, Candida albicans, Aspergillus niger, and Penicillium expansum.

N-[(1aR,5aR,8R,9aR)-1,1-Dichloro-1a,5,5,7-tetramethyl-1a,2,3,4,5,5a,8,9-octahydro-1H-benzo[a]cyclopropa[b][7]annulen-8-yl]acetamide

In the title compound, C18H27Cl2NO, the cyclohexene ring has an envelope conformation, with the C atom at the 9a position as the flap. The cycloheptane ring, to which it is fused, has a boat conformation. The dihedral angle between their mean planes is 60.7 (2)°. The 1,1-dichloro-cyclopropane ring is inclined to these two ring mean planes by 88.5 (3) and 28.3 (3)°, respectively. In the crystal, molecules are linked by N—H...O hydrogen bonds, forming 61helices along thec-axis direction. The absolute configuration of the molecule in the crystal could be fully confirmed from anomalous dispersion effects [Flack parameter = 0.020 (15)].

(2E)-N-Methyl-2-[1-(4-methylcyclohex-3-en-1-yl)ethylidene]hydrazinecarbothioamide

There are two independent molecules (AandB) in the asymmetric unit of the title compound, C11H19N3S. In moleculeB, two C atoms and the associated H atoms of the cyclohexene ring are disordered over two sets of sites with a site occupancy ratio of 0.649 (7):0.351 (7). The N—N—C—N fragments of the hydrazinecarbothioamide segments of both molecules are not planar, with a torsion angle of −5.8 (3)° forAand 11.6 (3)° forB. The stability of the conformations of both molecules is aided by the formation of intramolecular N—H...N hydrogen bonds. In the crystal, N—H...S hydrogen bonds link like molecules intoR22(8)A+Bdimers. These dimers are interconnected by additional N—H...S contacts, forming chains along thec-axis direction. The structure was refined as a two-component inversion twin.