Man Chun Law

Solvent-free route to ionic liquid precursors using a water-moderated microwave process

Water moderation has been used for solvent-free microwave assisted reactions which generate over-heating. The method is demonstrated by the large scale preparation of ionic liquid precursors.

Metal mediated allylation of carbonyl compounds in ionic liquids

In, Sn and Zn metals mediate the allylation of carbonyl compounds in [bmim][BF4] or [emim][BF4] to give the corresponding homoallylic alcohols in good to excellent yields. Tin was found to be the metal of choice among the metals examined.

Organometallic reactions in ionic liquids. Alkylation of aldehydes with diethylzinc

The ionic liquids, [bmim][Br] n (2a), [bmim][BF4] n (2b), [bmim][PF6] n (2c), [bdmim][BF4] n (8) and [bpy][BF4] n (9), were examined as the solvent media for dialkylzinc addition to aldehydes giving the corresponding alcohols. The ionic liquid [bpy][BF4] was found to be the solvent of choice, giving the best yields, easily recovered and reused.

Grignard reagents in ionic liquids

Grignard reagents were generated from magnesium and organic iodides in the ionic liquid n-butylpyridinium tetrafluoroborate, [bpy][BF4], and they showed different reactivity from classical Grignard reagents in organic solvents.

Development of a UPLC-MS/MS bioanalytical method for the pharmacokinetic study of (-)-epiafzelechin, a flavan-3-ol with osteoprotective activity, in C57BL/6J mice.

(-)-Epiafzelechin is a flavan-3-ol commonly found in plant source. Biological studies suggested that (-)-epiafzelechin may have anti-inflammatory, anti-oxidant and bone-protective effect. However, its in vivo efficacy remains to be demonstrated. A specific detection method for (-)-epiafzelechin was successfully developed by using UPLC-MS/MS to quantify the amount of (-)-epiafzelechin present in mice plasma after a liquid-liquid extraction by ethyl acetate. The separation was achieved by using a reversed-phase C18 column with a 16 min gradient elution protocol consisting of water (0.1%, v/v, formic acid) and 0-70% ACN (0.1%, v/v, formic acid). The lower limit of quantitation for (-)-epiafzelechin was found to be 12.5 ng/mL. This method exhibited a good linearity (r(2)=0.992). The intra-day and inter-day precision were within 12%, while the accuracy was between 97.6 and 113. 4%. A quantity of 10mg/kg synthetic (-)-epiafzelechin was administered to C57BL/6J mice by intravenous (i.v.) and intraperitoneal (i.p.) injections and the blood was collected at different time points. The plasma was then analyzed by the UPLC-MS/MS method, and the plasma drug concentration-time curves for i.v. and i.p. (-)-epiafzelechin injection were constructed. The maximum concentrations (Cmax) of (-)-epiafzelechin in blood by i.v. and i.p. injection were found to be 10.6 and 6.0 μg/mL, respectively, while the time for reaching Cmax in i.p. injection was found to be 15 min. The distribution half-lives of (-)-epiafzelechin after i.v. and i.p. injection were found to be 7.0 and 12.6 min, respectively. Some of the PK parameters were found to be similar in both i.v. and i.p. injections of (-)-epiafzelechin owing to its high solubility in water.

A New Class of Safe, Potent, and Specific P-gp Modulator: Flavonoid Dimer FD18 Reverses P-gp-Mediated Multidrug Resistance in Human Breast Xenograft in Vivo

Flavonoid dimer FD18 is a new class of dimeric P-gp modulator that can reverse cancer drug resistance. FD18 is a potent (EC50 = 148 nM for paclitaxel), safe (selective index = 574), and selective P-glycoprotein (P-gp) modulator. FD18 can modulate multidrug resistance toward paclitaxel, vinblastine, vincristine, doxorubicin, daunorubicin, and mitoxantrone in human breast cancer LCC6MDR in vitro. FD18 (1 μM) can revert chemosensitivity of LCC6MDR back to parental LCC6 level. FD18 was 11- to 46-fold more potent than verapamil. FD18 (1 μM) can increase accumulation of doxorubicin by 2.7-fold, daunorubicin (2.1-fold), and rhodamine 123 (5.2-fold) in LCC6MDR. FD18 inhibited P-gp-mediated doxorubicin efflux and has no effect on influx. FD18 at 1 μM did not affect the protein expression level of P-gp. Pharmacokinetics studies indicated that intraperitoneal administration of 45 mg/kg FD18 was enough to maintain a plasma level above EC50 (148 nM) for more than 600 min. Toxicity studies with FD18 (90 mg/kg, i.p. for 12 times in 22 days) with paclitaxel (12 mg/kg, i.v. for 12 times in 22 days) revealed no obvious toxicity or death in mice. In vivo efficacy studies indicated that FD18 (45 mg/kg, i.p. for 12 times in 22 days) together with paclitaxel (12 mg/kg, i.v. for 12 times in 22 days) resulted in a 46% reduction in LCC6MDR xenograft volume (n = 11; 648 ± 84 mm(3)) compared to paclitaxel control (n = 8; 1201 ± 118 mm(3)). There were no animal deaths or significant drop in body weight and vital organ wet weight. FD18 can increase paclitaxel accumulation in LCC6MDR xenograft by 1.8- to 2.2-fold. The present study suggests that FD18 represents a new class of safe and potent P-gp modulator in vivo.

Chemical synthesis and biological study of 4β-carboxymethyl-epiafzelechin acid, an osteoprotective compound from the rhizomes of Drynaria fortunei

The chemically synthesized active osteoprotective component 12 of Drynaria fortunei (kunze) J. Sm showed potent proliferative activity on UMR-106 osteoblast-like cells and selectively activate ERE-dependent gene transcription mediated by ERα but not ERβ.

Discovery of novel flavonoid dimers to reverse multidrug resistance protein 1 (MRP1; ABCC1)-mediated drug resistance in cancers using a high throughput platform with “click chemistry”

A 300-member flavonoid dimer library of multidrug resistance-associated protein 1 (MRP1, ABCC1) modulators was rapidly assembled using click chemistry. Subsequent high-throughput screening has led to the discovery of highly potent (EC50 ranging from 53 to 298 nM) and safe (selective indexes ranging from >190 to >1887) MRP1 modulators. Some dimers have potency about 6.5- to 36-fold and 64- to 358-fold higher than the well-known MRP1 inhibitors, verapamil, and MK571, respectively. They inhibited DOX efflux and restored intracellular DOX concentration. The most potent modulator, Ac3Az11, was predicted to bind to the bipartite substrate-binding site of MRP1 in a competitive manner. Moreover, it provided sufficient concentration to maintain its plasma level above its in vitro EC50 (53 nM for DOX) for about 90 min. Overall, we demonstrate that click chemistry coupled with high throughput screening is a rapid, reliable, and efficient tool in the discovery of compounds having potent MRP1-modualting activity.