In vitro screening of 1-aryl-6-hydroxy-1,2,3,4-tetrahydroisoquinolines: structure related activity against pathogenic bacteria

Objective: To evaluate the antibacterial activity of ten synthetic tetrahydroisoquinolines against eight bacterial strains. Methods: The ten tetrahydroisoquinolines synthesized via base-catalyzed Pictet-Spengler cyclization were screened against a total of eight bacterial strains comprising control and pathogenic strains by the disc diffusion and micro-dilution methods. The most active compound was then assessed for cytotoxicity on human lymphocytes. Results: Six of the tetrahydroisoquinolines showed broad spectrum bacteriostatic activity. The zones of inhibition produced ranged from 7 to 23 mm for 200 μg per disc. The presence of a lipophilic substituent at the para position of the pendant phenyl group conferred the highest antibacterial activity. Compound 2 [1-(3,4-chlorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline] was the most active and produced zones ranging from 9 to 20 mm against all eight bacterial strains. Compound 2 also showed the lowest minimum inhibitory concentration of 100 μg/mL against Escherichia coli ATCC11775 and the lowest minimum bactericidal concentration of 800 μg/mL against pathogenic Salmonella typhimurium. Overall, compound 2 was the most active with bacteriostatic and bactericidal activity against three and four bacterial strains respectively. A 50% cytotoxic concentration of 98.2 μg/mL was recorded for compound 2 indicating a low risk of toxicity. Conclusions: The 1-aryl-1,2,3,4-tetrahydroisoquinolines display structure-related antibacterial activity and further chemical exploration of the tetrahydroisoquinoline scaf old may yield more potent non-toxic derivatives for development into new antibacterials.

Enantioselective addition of diethylzinc to aryl aldehydes catalyzed by 1,2,3,4-tetrahydroisoquinoline β-amino alcohol

A highly effective,new chiral 1,2,3,4-tetrahydroisoquinoline catalyst 1 for the diethylzinc addition to aryl aldehydes has been investigated.Using 10 mol%of this chiral catalyst,secondary alcohols can be obtained in up to 87%yield and 99.5%ee under mild conditions.

1-Chloromethyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-sulfonic acid amide, a derivative of tetrahydroisoquinoline, induces granulocytic differentiation of the human leukemic HL-60 cells via G0/G1 phase arrest

Tetrahydroisoquinolines are known to have various biological effects, including antitumor activity. This study investigated the effect of 1-chloromethyl-6, 7-dimethoxy-3, 4-dihydro-1H-isoquinoline-2-sulfonic acid amide (CDST), a newly synthesized anticancer agent, on cellular differentiation and proliferation in HL-60 cells. Differentiation and proliferation of HL-60 cells were determined through expression of CD11b and CD14 surface antigens using flow cytometry and nitroblue tetrazolium (NBT) assay, and through analysis of cell cycle using propidium iodide staining, western blot analysis and immunoprecipitation, respectively. CDST induced the differentiation of HL-60, as shown by increased expression of differentiation surface antigen CD11b (but no significant change in CD14 expression) and increased NBT-reducing functional activity. DNA flow cytometry analysis indicated that CDST markedly induced a G0/G1 phase arrest of HL-60 cells. Subsequently, we examined the expre-ssion of G0/G1 phase cell cycle-related proteins, including cyclin-dependent kinases (CDKs), cyclins and cyclin dependent kinase inhibitors (CKIs), during the differentiation of HL-60. The levels of CDK2, CDK6, cyclin E and cyclin A were decreased, whereas steady-state levels of CDK4 and cyclin D1 were unaffected. The expression of the p27Kip1 was markedly increased by CDST, but not p21WAF1/Cip1. Moreover, CDST markedly enhanced the binding of p27Kip1 with CDK2 and CDK6, resulting in the reduced activity of both kinases. Taken together, these results demonstrate that CDST is capable of inducing cellular differentiation and growth inhibition through p27Kip1 protein-related G0/G1 phase arrest in HL-60 cells.

Synthesis and Evaluation of Anticonvulsant Activity of 6,8-Dimethoxy-3-methyl-1,2,3,4-tetrahydroisoquinoline in PTZ-Induced Seizure Model in Mice

This study we describe the synthesis of a novel structure of anticonvulsant agent as 6,8-dimethoxy-3-methyl-1,2,3,4- tetrahydroisoquinoline by using GYKI52466, which was the potent anticonvulsant agent, as the lead molecule. Com-pound IV was synthesized and anticonvulsant effects was evaluated against Pentylenetetrazole (PTZ)-induced seizure model in mice. The acute anticonvulsant effect was tested with a single dose of 25 and 75 μmol/kg of the synthesis compound. Sodium valproate and normal saline were used as the reference standard and control, respectively. All compounds were injected intraperitoneally to each mouse an hour prior to seizure induced by injection of 60 mg/kg PTZ and observed their behavior for 30 minutes. The result showed that the IV at 75 μmol/kg could delay the latency to first twitch and decrease percent mortality compared to control group.

Determination of Enantiomeric Composition of Substituted Tetrahydroisoquinolines Based on Derivatization with Menthyl Chloroformate

A method for the analysis of the optical purity of a series of chiral substituted tetrahydroisoquinolines (THIQs) was developed. The method is based on pre-column derivatization of the analytes with the derivatization reagent (–)-(1R)-menthyl chloroformate. The derivatization reaction selectively gives diastereomeric carbamates that are resolvable on an achiral non-polar GC column. The developed technique covers variously substituted THIQs, which differ significantly in volatility, steric and electronic properties. In all cases, the resolution factors (R) exceeded the value of 1.5. The method represents a robust way of analysis of mixtures of THIQs, which are often present in various matrixes such as body fluids, tissues and reaction mixtures.

Tetrahydroisoquinolines as novel histone deacetylase inhibitors for treatment of cancer

Histone acetylation is a critical process in the regulation of chromatin structure and gene expression.Histone deacetylases(HDACs)remove the acetyl group,leading to chromatin condensation and transcriptional repression.HDAC inhibitors are considered a new class of anticancer agents and have been shown to alter gene transcription and exert antitumor effects.This paper describes our work on the structural determination and structure-activity relationship(SAR)optimization of tetrahydroisoquinoline compounds as HDAC inhibitors.These compounds were tested for their ability to inhibit HDAC 1,3,6 and for their ability to inhibit the proliferation of a panel of cancer cell lines.Among these,compound 82 showed the greatest inhibitory activity toward HDAC 1,3,6 and strongly inhibited growth of the cancer cell lines,with results clearly superior to those of the reference compound,vorinostat(SAHA).Compound 82 increased the acetylation of histones H3,H4 and tubulin in a concentration-dependent manner,suggesting that it is a broad inhibitor of HDACs.

Integrating photocatalytic reduction of CO2 with selective oxidation of tetrahydroisoquinoline over InP–In2O3 Z-scheme p-n junction

The development of a facile strategy to construct stable hierarchal porous heterogeneous photocatalysts remains a great challenge for efficient CO2 reduction.Additionally,hole-trapping sacrificial agents(e.g.,triethanolamine,triethylamine,and methanol)are mostly necessary,which produce useless chemicals,and thus cause costs/environmental concerns.Therefore,utilizing oxidation ability of holes to develop an alternative photooxidation reaction to produce value-added chemicals,especially coupled with CO2 photoreduction,is highly desirable.Here,an in situ partial phosphating method of In2O3 is reported for synthesizing In P–In2O3 p-n junction.A highly selective photooxidation of tetrahydroisoquinoline(THIQ)into value-added dihydroisoquinoline(DHIQ)is to replace the hole driven oxidation of typical sacrificial agents.Meanwhile,the photoelectrons of In P–In2O3 p-n junction can induce the efficient photoreduction of CO2 to CO with high selectivity and stability.The evolution rates of DHIQ and CO are 2 and 3.8 times higher than those of the corresponding In2O3 n-type precursor,respectively.In situ irradiated X-ray photoelectron spectroscopy and electron spin resonance are utilized to confirm that the direct Z-scheme mechanism of In P–In2O3 p-n junction accelerate the efficient separation of photocarriers.

Synthesis of tetrahydroisoquinolines through TiCl4-mediated cyclization and Et3SiH reduction

A versatile and efficient telescoped reaction sequence for the synthesis of tetrahydroisoquinolines(THIQs)is reported that uses TiCl4 to promote cyclization of a benzylaminoacetal derivative and Et3SiH for reduction of the intermediate 4-hydroxy-THIQ.This method is complimentary to the classical Pomeranz-Fritsch and related reactions since it tolerates electron-withdrawing substituents and allows access to 8-substituted THIQs.

Dihydrofolate reductase-like protein inactivates hemiaminal pharmacophore for self-resistance in safracin biosynthesis

Dihydrofolate reductase(DHFR),a housekeeping enzyme in primary metabolism,has been extensively studied as a model of acid-base catalysis and a clinic drug target.Herein,we investigated the enzymology of a DHFR-like protein SacH in safracin(SAC)biosynthesis,which reductively inactivates hemiaminal pharmacophore-containing biosynthetic intermediates and antibiotics for self-resistance.Furthermore,based on the crystal structure of SacH−NADPH−SAC-A ternary complexes and mutagenesis,we proposed a catalytic mechanism that is distinct from the previously characterized short-chain dehydrogenases/reductases-mediated inactivation of hemiaminal pharmacophore.These findings expand the functions of DHFR family proteins,reveal that the common reaction can be catalyzed by distinct family of enzymes,and imply the possibility for the discovery of novel antibiotics with hemiaminal pharmacophore.

Efficient and Practical Syntheses of Enantiomerically Pure (S)-(−)-Norcryptostyline Ⅰ, (S)-(−)-Norcryptostyline Ⅱ, (R)-(+)-Salsolidine and (S)-(−)-Norlaudanosine via a Resolution-Racemization Method

Four racemic tetrahydroisoquinolines(RS)-(±)-1-4 were prepared from homoveratrylamine via amidation,Bischler-Napieralski reaction and the subsequent reduction.The enantiomerically pure tetrahydroisoquinolines(S)-(−)-norcryptostyline Ⅰ[(S)-(−)-1],(S)-(−)-norcryptostyline Ⅱ[(S)-(−)-2],(R)-(+)-salsolidine[(R)-(+)-3]and(S)-(−)-norlaudanosine[(S)-(−)-4]were then obtained in 45%,40%,41%and 38%yields,respectively,via resolution of the racemic compounds(RS)-(±)-1-4 with half equivalent of chiral acids.In addition,the enantiomerically enriched compounds(R)-(+)-1,(R)-(+)-2,(S)-(−)-3 and(R)-(+)-4 from the mother liquors were efficiently racemized via a one-pot redox method in almost quantitative yields.