Design and synthesis of 6-C-alkyl-DMDP type nanomolar inhibitors of ß-galactosidase and ß-glucosidase based on broussonetine S and related derivatives.

Broussonetine S (9), its C-1' and C-10' stereoisomers, and their corresponding enantiomers have been synthesized from enantiomeric arabinose-derived cyclic nitrones, with cross metathesis (CM), epoxidation and Keck asymmetric allylation as key steps. Glycosidase inhibition assays showed that broussonetine S (9) and its C-10' epimer (10'-epi-9) were nanomolar inhibitors of bovine liver ß-galactosidase and ß-glucosidase; while their C-1' stereoisomers were 10-fold less potent towards these enzymes. The glycosidase inhibition results and molecular docking calculations revealed the importance of the configurations of pyrrolidine core and C-1' hydroxyl for inhibition potency and spectra. Together with the docking calculations we previously reported for α-1-C-alkyl-DAB derivatives, we designed and synthesized a series of 6-C-alkyl-DMDP derivatives with very simple alkyl chains. The inhibition potency of these derivatives was enhanced by increasing the length of the side chain, and maintained at nanomolar scale inhibitions of bovine liver ß-glucosidase and ß-galactosidase after the alkyl groups are longer than eight or ten carbons for the (6R)-C-alkyl-DMDP derivatives and their 6S epimers, respectively. Molecular docking calculations indicated that each series of 6-C-alkyl-DMDP derivatives resides in the same active site of ß-glucosidase or ß-galactosidase with basically similar binding conformations, and their C-6 long alkyl chains extend outwards along the hydrophobic groove with similar orientations. The increasing inhibitions of ß-glucosidase and ß-galactosidase with the number of carbon atoms in the side chains may be explained by improved adaptability of longer alkyl chains in the hydrophobic grooves. In addition, the lower ß-glucosidase and ß-galactosidase inhibitions of (6S)-C-alkyl-DMDP derivatives than their C-6 R stereoisomers can be attributed to the misfolding of their alkyl chains and resulted decreased adaptability in the hydrophobic groove. The work reported herein is valuable for design and development of more potent and selective inhibitors of ß-galactosidase and ß-glucosidase, which have potential in treatment of lysosomal storage diseases. Furthermore, part of the 6-C-alkyl-DMDP derivatives and their enantiomers were also tested as potential anti-cancer agents; all the compounds tested were found with moderate cytotoxic effects on MKN45 cells, which would indicate potential applications of these iminosugars in development of novel anticancer agents.

PhI(OAc)2/Pd(OAc)2 promoted the formation of 8-hydroxyquinoline derivatives from benzoxazoles and alcohols.

A PhI(OAc)2/Pd(OAc)2 system that synergistically promotes the formation of 8-hydroxyquinoline derivatives from benzoxazoles and alcohols has been developed. The reaction proceeded smoothly with a range of benzoxazoles and alcohols to give the corresponding 8-hydroxyquinoline derivatives in moderate yields.

Four-Objective Optimization of an Irreversible Magnetohydrodynamic Cycle.

Based on the existing model of an irreversible magnetohydrodynamic cycle, this paper uses finite time thermodynamic theory and multi-objective genetic algorithm (NSGA-II), introduces heat exchanger thermal conductance distribution and isentropic temperature ratio of working fluid as optimization variables, and takes power output, efficiency, ecological function, and power density as objective functions to carry out multi-objective optimization with different objective function combinations, and contrast optimization results with three decision-making approaches of LINMAP, TOPSIS, and Shannon Entropy. The results indicate that in the condition of constant gas velocity, deviation indexes are 0.1764 acquired by LINMAP and TOPSIS approaches when four-objective optimization is performed, which is less than that (0.1940) of the Shannon Entropy approach and those (0.3560, 0.7693, 0.2599, 0.1940) for four single-objective optimizations of maximum power output, efficiency, ecological function, and power density, respectively. In the condition of constant Mach number, deviation indexes are 0.1767 acquired by LINMAP and TOPSIS when four-objective optimization is performed, which is less than that (0.1950) of the Shannon Entropy approach and those (0.3600, 0.7630, 0.2637, 0.1949) for four single-objective optimizations, respectively. This indicates that the multi-objective optimization result is preferable to any single-objective optimization result.

Discovery of a new class of multi-target heterocycle piperidine derivatives as potential antipsychotics with pro-cognitive effect.

A series of benzoisoxazoleylpiperidine derivatives were synthesized by using the multi-target strategies and their potent affinities for dopamine (DA), serotonin (5-HT) and human histamine H3 receptors have been evaluated. Of these compounds, the promising candidate 4w displayed high affinities for D2, D3, 5-HT1A, 5-HT2A and H3, a moderate affinity for 5-HT6, negligible effects on the human ether-a-go-go-related gene (hERG) channel, low affinities for off-target receptors (5-HT2C, adrenergic α1 and H1). In addition, the animal behavioral study revealed that, compared to risperidone, compound 4w significantly inhibited apomorphine-induced climbing and MK-801-induced movement behaviors with a high threshold for catalepsy and low liabilities for weight gain and hyperprolactinemia. Results from the conditioned avoidance response test and novel object recognition task demonstrated that 4w had pro-cognitive effects. Thus, the antipsychotic drug-like activities of 4w indicate that it may be a potential polypharmacological antipsychotic candidate drug.

Synthesis and Glycosidase Inhibition of Broussonetine M and Its Analogues.

Cross-metathesis (CM) and Keck asymmetric allylation, which allows access to defined stereochemistry of a remote side chain hydroxyl group, are the key steps in a versatile synthesis of broussonetine M (3) from the d-arabinose-derived cyclic nitrone 14. By a similar strategy, ent-broussonetine M (ent-3) and six other stereoisomers have been synthesized, respectively, starting from l-arabino-nitrone (ent-14), l-lyxo-nitrone (ent-3-epi-14), and l-xylo-nitrone (2-epi-14) in five steps, in 26%-31% overall yield. The natural product broussonetine M (3) and 10'-epi-3 were potent inhibitors of ß-glucosidase (IC50 = 6.3 µM and 0.8 µM, respectively) and ß-galactosidase (IC50 = 2.3 µM and 0.2 µM, respectively); while their enantiomers, ent-3 and ent-10'-epi-3, were selective and potent inhibitors of rice α-glucosidase (IC50 = 1.2 µM and 1.3 µM, respectively) and rat intestinal maltase (IC50 = 0.29 µM and 18 µM, respectively). Both the configuration of the polyhydroxylated pyrrolidine ring and C-10' hydroxyl on the alkyl side chain affect the specificity and potency of glycosidase inhibition.

Synthesis, structural characterization and in vitro cytotoxicity of diorganotin (IV) diimido complexes.

Reactions of the diorganotin with two N-OH diimide ligands (N-hydroxyphthalimide and N-hydroxysuccinimide) yielded five new dimeric tetraorganostannoxanes formulated as R(8)Sn(4)O(2)L(2)X(2). The crystal structures of the complexes reveal the formation of the tetranuclear species contains a planar Sn(4)O(4) core, consisting of three adjacent rhombs with bridging oxo and N-OH diimide ligands. The central tin atoms are five-coordinated to assume a distorted trigonal bipyramidal configuration and the N-OH diimide ligands act as monodentate O-bound planar. In vitro cytotoxic activities of the title compounds have been determined against three cell lines (A549, HCT-8 and HL-60). Studies reveal that three di-n-butyltin(IV) diimido complexes show higher cytotoxic activities than cisplatin. The structure-activity relationship of the cytotoxicity of the title complexes has also been discussed.

Bis(acetohydroxamato-κO,O')diphenyl-tin(IV).

The complex mol-ecule of the title compound, [Sn(C(6)H(5))(2)(C(2)H(4)NO(2))(2)], has crystallographically imposed twofold symmetry. The Sn atom is coordinated by four O atoms from two acetohydroxamate ligands and by two C atoms from phenyl groups in a distorted octa-hedral geometry. In the crystal, mol-ecules are connected by N-H⋯O hydrogen-bonding inter-actions, forming a chain structure along the c axis.

N-Hy-droxy-pyridine-4-carboxamide.

The title compound, C(6)H(6)N(2)O(2), is approximately planar with an r.m.s. deviation for the non-H atoms of 0.052 Å. In the crystal, a two-dimensional array in the bc plane is stabilized by O-H⋯N and N-H⋯O hydrogen bonds.

3-Hy-droxy-N'-[(E)-3-pyridyl-methyl-idene]-2-naphtho-hydrazide.

The title compound, C(17)H(13)N(3)O(2), displays an E configuration about the C=N bond. The mean planes of the pyridine and benzene rings make a dihedral angle of 31.2 (2)°. An intra-molecular O-H⋯O hydrogen bond is observed. In the crystal, inter-molecular N-H⋯N hydrogen bonding links the mol-ecules into a chain along [101].

3-Hy-droxy-N'-[(E)-2-thienyl-methyl-idene]-2-naphtho-hydrazide.

The asymmetric unit of the title compound, C(16)H(12)N(2)O(2)S, contains three independent mol-ecules. Intra-molecular N-H⋯O hydrogen bonds in the three mol-ecules lead to very similar conformations: the thio-pene ring and naphthalene ring system in the three mol-ecules form dihedral angles of 10.3 (2), 9.1 (2) and 9.3 (3)°. In the crystal structure, inter-molecular O-H⋯O hydrogen bonds link the mol-ecules into chains propagating in [031].