New ε-N-thioglutaryl-lysine derivatives as SIRT5 inhibitors: Chemical synthesis, kinetic and crystallographic studies.

SIRT5 has been implicated in various physiological processes and human diseases, including cancer. Development of new highly potent, selective SIRT5 inhibitors is still needed to investigate disease-related mechanisms and therapeutic potentials. We here report new ε-N-thioglutaryllysine derivatives, which were designed according to SIRT5-catalysed deacylation reactions. These ε-N-thioglutaryllysine derivatives displayed potent SIRT5 inhibition, of which the potential photo-crosslinking derivative 8 manifested most potent inhibition with an IC50 value of 120 nM to SIRT5, and low inhibition to SIRT1-3 and SIRT6. The enzyme kinetic assays revealed that the ε-N-thioglutaryllysine derivatives inhibit SIRT5 by lysine-substrate competitive manner. Co-crystallographic analyses demonstrated that 8 binds to occupy the lysine-substate binding site by making hydrogen-bonding and electrostatic interactions with SIRT5-specific residues, and is likely positioned to react with NAD+ and form stable thio-intermediates. Compound 8 was observed to have low photo-crosslinking probability to SIRT5, possibly due to inappropriate position of the diazirine group as observed in SIRT5:8 crystal structure. This study provides useful information for developing drug-like inhibitors and cross-linking chemical probes for SIRT5-related studies.

Design, Synthesis, and Activity Study of Water-Soluble, Rapid-Release Propofol Prodrugs.

In this work, a series of water-soluble propofol prodrugs were synthesized, and their propofol release rate and pharmacodynamic characteristics were measured. We found that inserting glycolic acid as a linker between propofol and the cyclic amino acid accelerated the release of propofol from prodrugs into the plasma while preserving its safety. In animal experiments, prodrugs (3e, 3g, and 3j) were significantly better than fospropofol (the only water-soluble propofol prodrug that has been used clinically) in terms of safety, onset, and duration time of anesthesia. Their molar dose, onset time, and anesthesia duration time were comparable to those of propofol, helping to maintain the clinical benefits of propofol. The experimental results showed the potential of such compounds as water-soluble prodrugs of propofol.

Synthesis and antibacterial activity of new fluoroquinolones containing a cis- or trans-cyclohexane moiety.

New quinolone derivatives bearing a cis- or trans-cyclohexane side chain at the C-7 position have been synthesized and evaluated for their antibacterial activities against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa using the agar dilution method. The activities of compound 53 against these three bacteria were superior to those of the reference drug lomefloxacin. Compounds bearing a cis-cyclohexane side chain generally exhibited greater antibacterial activity than their corresponding trans-isomers.

[3-Bromo-meth-yl-1-(4-methyl-phenyl-sulfon-yl)azetidin-3-yl]methanol.

The asymmetric unit of the title compound, C(12)H(16)BrNO(3)S, contains two independent mol-ecules. In each mol-ecule, the azetidine four-membered ring adopts a nearly planar conformation, the maximum deviations being 0.087 (3) and 0.079 (3) Å. The mean azetidine plane is twisted by 75.2 (2) and 73.6 (2)° with respect to the plane of the benzene ring in the two independent mol-ecules. The crystal packing is stabilized by O-H⋯O hydrogen bonds.

A general synthetic procedure for 2-chloromethyl-4(3H)-quinazolinone derivatives and their utilization in the preparation of novel anticancer agents with 4-anilinoquinazoline scaffolds.

In our ongoing research on novel anticancer agents with 4-anilinoquinazoline scaffolds, a series of novel 2-chloromethyl-4(3H)-quinazolinones were needed as key intermediates. An improved one-step synthesis of 2-chloromethyl-4(3H)-quinazolinones utilizing o-anthranilic acids as starting materials was described. Based on it, 2-hydroxy-methyl-4(3H)-quinazolinones were conveniently prepared in one pot. Moreover, two novel 4-anilinoquinazoline derivatives substituted with chloromethyl groups at the 2-position were synthesized and showed promising anticancer activity in vitro.

3,3'-[(tert-Butoxy-carbon-yl)aza-nedi-yl]dipropanoic acid.

The title compound, C(11)H(19)NO(6), is an important inter-mediate for the synthesis of cephalosporin derivatives. The N atom is in a planar configuration. In the crystal, mol-ecules are linked into zigzag layers parallel to (100) by O-H⋯O hydrogen bonds.

trans-4-Nitro-phenyl 4-(tosyl-oxymeth-yl)cyclo-hexa-necarboxyl-ate.

The title compound, C(21)H(23)NO(7)S, is an important inter-mediate in the synthesis of poly(amido-amine) dendrimers. The cyclo-hexane ring adopts a chair conformation. The dihedral angle between the two aromatic rings is 69.5 (2)°. The mol-ecules are linked into a zigzag chain along the b axis by C-H⋯O hydrogen bonds.

trans-4-(Tosyl-oxymeth-yl)cyclo-hexane-carboxylic acid.

The title compound, C(15)H(20)O(5)S, is an inter-mediate in the synthesis of a new type of poly(amido-amine) (PAMAM) dendrimer. The cyclo-hexane ring exhibits a chair conformation, with C-C bond lengths in the range 1.518 (3)-1.531 (3) Šand C-C-C angles in the range 110.45 (19)-112.09 (19)°; these agree well with the values in other cyclo-hexane derivatives described in the literature. In the crystal structure, adjacent mol-ecules are linked by O-H⋯·O hydrogen bonds. The H atoms of the methyl group are disordered equally over two positions.

trans-4-[(Phenyl-sulfon-yloxy)meth-yl]cyclo-hexa-necarboxylic acid.

The title compound, C(14)H(18)O(5)S, is an important inter-mediate for the synthesis of poly(amido-amine) dendrimers. The cyclo-hexane ring adopts a chair conformation with its two substituents in equatorial positions. In the crystal structure, mol-ecules form centrosymmetric dimers via O-H⋯O hydrogen bonds.

trans-4-(Phenoxy-meth-yl)cyclo-hexane-carboxylic acid.

The title compound, C(14)H(18)O(3), is an important model compound in the synthesis of phenolic ethers. The cyclo-hexane ring adopts a chair conformation. In the crystal structure, adjacent mol-ecules are linked by O-H⋯O hydrogen bonds.