Tetrahydroisoquinoline Derivatives Research Articles

Catalyst‐Free Synthesis of Novel Dimeric Tetrahydroisoquinoline Derivatives through [2+2+2] Annulation

A simple, straightforward, and atom economic catalyst‐free [2+2+2] annulation of dihydroisoquinolines and allenoates has been developed. A diverse range of novel dimeric tetrahydroisoquinoline derivatives can be prepared in moderate to good yields (37–87 %) from readily available material. Dihydro‐β‐carboline can also be used in this reaction system delivering corresponding dimeric dihydro‐β‐carboline derivatives. Notably, the reaction could be easily scaled up to gram scale. The easy scale‐up of this process may provide structurally diversified natural product‐like molecules possessing privileged scaffold for potential application in biomedical research and other research fields. Interestingly, in contrast to the α,β‐selectivity observed in our previous study, β,γ‐selective [2+2+2] annulation was preferred in this work.

Abstract 22: Design and synthesis of substituted tetrahydroisoquinoline derivatives as anti-angiogenic and anti-breast cancer agents

Abstract Angiogenesis is the formation of new blood vessels and plays a critical role in the development, invasion and metastasis of breast cancer pathogenesis. Vascular Endothelial Growth Factor (VEGF) is one of the important angiogenic factors secreted by tumor cells. Overexpression of VEGF significantly increases tumor growth and angiogenesis in a murine model of breast cancer. Inhibition of VGEF pathway by limiting new blood vessels formation has proven to be a valuable approach in reducing tumor growth. During the last two decades, diversified small molecules were evaluated and developed as anti-angiogenic agents. Trabectedin (ET-743; Yondelis) is a tetrahydroisoquinoline alkaloid derived from a Caribbean tunicate Ecteinascidia turbinata and has a potent in vitro and in vivo antitumor activity, including prostate and breast cancers. Trabectedin significantly inhibited the mRNA and protein expression levels of VEGF in all breast cancer cells tested. Previously, we developed a series of tetrahydroisoquinoline (THIQs) derivatives and their in-vitro anti-proliferative activities were tested against MCF-7, MDA-MB-231 human breast cancer cell lines and Ishikawa human endometrial adenocarcinoma cell lines. These THIQ derivatives have the same core structure as that of Trabectedin alkaloid and are considered potential anti-angiogenic agents. Novel substituted THIQ derivatives were designed and synthesized in our laboratory. N-amination of substituted isoquinolines by the aminating agent, O-mesytelenesulfonylhydroxylamine and treated with acyl chlorides led to the formation of ylides. The ylides were reduced using sodium borohydride to yield the desired substituted tetrahydroisoquinolines in moderate to good yields. The synthesized compounds were characterized using NMR and elemental analysis. Of the synthesized compounds, fifteen compounds were screened for anti-angiogenesis activity in the Eli Lilly’s Open Innovation Drug Discovery Program (OIDD). Five compounds exhibited greater than 50% inhibition of the tube area at 10µM in the primary single point assay. These five compounds were further screened at different concentrations to obtain dose response curves and IC50 Values. Compound 4-ethyl-N-(3,4-dihydroisoquinolin-2(1H)-yl) benzamide showed an IC50 Value of 1.72 µM. This research was supported by the National Center for Research Resources and the National Institute of Minority Health and Health Disparities of the National Institutes of Health through Grant Number 8 G12MD007582-28. Citation Format: Kinfe Ken Redda, Madhavi Gangapuram, Suresh Eyuinni. Design and synthesis of substituted tetrahydroisoquinoline derivatives as anti-angiogenic and anti-breast cancer agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 22.

Synthesis and stereochemistry assignment of (3R,5R)- and (3S,5R)-4-benzyl-3-(3,4-dimethoxyphenyl)-5-phenyl-1,4-oxazin-2-ones

The diastereoselective synthesis of 3,5-disubstituted 1,4-oxazin-2-ones, the valuable intermediates on the route to tetrahydroisoquinoline derivatives, was based on the Petasis reaction in which (R)-(−)-N-benzyl-2-phenylglycinol was used as the amine component. It was demonstrated that the configuration of the newly generated C3 stereogenic centers in synthesized compounds, as well as in other 3,5-disubstituted 1,4-oxazin-2-ones, could be established simply by 1H NMR spectral data analysis. The absolute configuration of the major isomer was additionally confirmed by single crystal X-ray analysis.

Structural exploration of tetrahydroisoquinoline derivatives as HDAC8 inhibitors through multi-QSAR modeling study

Histone deacetylase 8 (HDAC8) is one of the crucial HDACs responsible for influencing the epigenetic functions of the body. Overexpression of HDAC8 is found to be involved in numerous disease conditions such as tumorigenesis, cell proliferation, cancer, viral infections, neuronal disorders and other epigenetic diseases. Therefore, inhibition of HDAC8 is a primary method to combat these diseases. In this article, a multi-QSAR modeling study on tetrahydroisoquinoline derivatives was conducted to identify important contributions of the structural features of these compounds toward HDAC8 inhibition. All these QSAR modeling techniques were individually validated and justified the observations of each other. The results implied that the tetrahydroisoquinoline moiety may be effective as a cap group than as a linker moiety for HDAC8 inhibition. Different substitutions at the tetrahydroisoquinoline scaffold were also found to be crucial in modulating HDAC8 inhibition.Communicated by Ramaswamy H. Sarma

Magnetic nanoparticle-supported eosin Y ammonium salt: An efficient heterogeneous catalyst for visible light oxidative C–C and C–P bond formation

A highly efficient visible light mediated C–C and C–P coupling reactions of sp3 C–H bonds adjacent to the nitrogen atom in tetrahydroisoquinoline derivatives with pronucleophiles such as nitroalkanes, malononitrile, dimethyl malonate and H-phosphonate diesters were achieved by using a magnetic nanoparticle-supported eosin Y bis-benzyltriethylammonium salt (MNPs-Eosin Y) as catalyst and air as the sole oxidant, affording the corresponding products in good to excellent yields under mild reaction conditions. Notably, the supported eosin Y catalyst can easily be separated from the reaction mixture by an external permanent magnet and can be recycled at least eight times without a significant loss of activity.

Synthesis and biological evaluation of F-18 labeled tetrahydroisoquinoline derivatives targeting orexin 1 receptor.

Orexin 1 receptor (OX1R) is thought to be involved in various body functions, including arousal maintenance and emotional control, but the full details of its function remain unknown. OX1R imaging with positron emission tomography (PET) would be useful in elucidating the orexin system including OX1R, but no PET probes targeting OX1R have been reported. We, therefore, designed and synthesized tetrahydroisoquinoline (THIQ) derivatives as novel PET probes targeting OX1R, and evaluated their utility. In an in vitro competitive binding assay, THIQ-1 and THIQ-2 showed significantly higher binding to OX1R (IC50 = 30 and 31 nM, respectively) than OX2R (IC50 = 160 and 332 nM, respectively). These features were also observed in a cell binding assay using [18F]THIQ-1 and [18F]THIQ-2, demonstrating their OX1R-specific binding property in vitro. In a biodistribution study using normal mice, the brain uptake of [18F]THIQ-1 was higher than that of [18F]THIQ-2, but further improvement is required for in vivo imaging with PET. Taken together, [18F]THIQ-1 and [18F]THIQ-2 have the potential to become useful imaging probes for PET targeting the OX1R, but require additional structural changes to improve their brain uptake.

Design and Synthesis of Bridging Chiral p–t‐Butylcalix[4]arene Tetrahydroisoquinolines and Their Application in Henry Reaction as Chiral Organocatalysts

AbstractA pair of bridging chiral p‐t‐butylcalix[4]arenes (2a and 2b) (were) synthesized from 1 through homologous anionic ortho‐Fries rearrangement, and optically resolved with (1S)‐(+)‐10‐camphorsulfonyl chloride as chiral auxiliary. Bridging chiral p‐t‐butylcalix[4]arene tetrahydroisoquinolines (9a and 9b) as chiral organocatalysts for Henry reaction were designed and synthesized through the structural modification of 2a and 2b, respectively. Compared to the catalytic enantioselectivity of the unmodified tertiary amine (4b: ∼0% ee and 63% yield), those of the tetrahydroisoquinoline derivatives (9b: up to 13.4% ee and 96% yield) were distinctly enhanced. Although the increase magnitude of the catalytic ee is not remarkable, these catalytic results prove that the conformation inversion of calix[4]arene skeleton and the rotational freedom reduction of catalytic amine group indeed bring beneficial effects on the catalytic stereoselectivity.

Multicomponent Reaction for Selective Synthesis of Spiro[indene‐2,7′‐isoquinoline] and 1,2,8,8 a‐Tetrahydroisoquinoline Derivatives

AbstractThe piperidine promoted three‐component reaction of N‐alkylpiperidin‐4‐ones, malononitrile and 2‐arylidene‐1,3‐indanediones in ethanol selectively resulted in the spiro[indene‐2,7′‐isoquinoline] and the ring‐opened cis‐ or trans‐1,2,8,8a‐tetrahydroisoquinoline derivatives at room temperature or at the elevated temperature. However, the four‐component reaction N‐alkylpiperidin‐4‐ones, malononitrile, aromatic aldehydes and 1,3‐indanedione in refluxing ethanol mainly afforded ring‐opened cis‐1,2,8,8a‐tetrahydroisoquinoline derivatives in good yields and with high diastereoselectivity. A plausible domino reaction mechanism was proposed for the formation of the different polycyclic products.

Synthesis of Functionalised Indoline and Isoquinoline Derivatives through a Silylcarbocyclisation/Desilylation Sequence

AbstractA two steps sequence of silylcarbocyclisation‐TBAF promoted desilylation/aryl migration has been applied to the synthesis of indolines and tetrahydroisoquinolines derivatives starting from suitable tosylamides and aryldimethylsilanes. In both cases silylcarbocyclisation reactions determined the formation of the heterocyclic ring together with the insertion of a CO functionality. Under the experimental conditions the carbonyl moiety is reduced to OH quantitatively. Subsequent treatment of silylated indolinols with TBAF generates stereoselectively the corresponding arylmethyl‐tosylindolinols. In the case of tetrahydroisoquinolinols, during the desilylation step, migration of the aryl moiety is followed by spontaneous loss of water thus affording 3,4‐dihydroisoquinolines exclusively.

Tetrahydroisoquinoline Sulfamates as Potent Microtubule Disruptors: Synthesis, Antiproliferative and Antitubulin Activity of Dichlorobenzyl-Based Derivatives, and a Tubulin Cocrystal Structure.

Tetrahydroisoquinoline (THIQ) 6-O-sulfamate-based anticancer agents, inspired by the endogenous steroid 2-methoxyestradiol and its sulfamate derivatives, are further explored for antiproliferative and microtubule disruptor activity. Based on recently designed C3-methyl C7-methoxy-substituted THIQ derivatives, compounds with mono- and dichloro-substitutions on the pendant N-benzyl ring were synthesized and evaluated. Although improved antiproliferative activity was observed, for example, 4a versus 4b and 4b versus 8c, it was relatively modest. Compound 8c, a 2′,5′-dichlorobenzyl derivative was, however, identified as a promising antiproliferative agent with in vitro activities exceeding that of the parent steroid (e.g., GI50 90 nM in DU-145 cells) and was highly potent against a range of tumor cell lines (e.g., GI50 26 nM for OVCAR-3). 8c inhibited the polymerization of tubulin in vitro with an IC50 only twofold less potent than combretastatin A-4 and inhibited colchicine binding to tubulin. Tubulin polymerization assays showed the parent THIQ 4a to be only a very weak inhibitor, but a striking potency difference was seen between compounds with C2′ methoxy and chloro substituents, whereas this was much smaller when these substituents were positioned at C5′. To confirm the target in atomic detail and because 8c is a racemic mixture, an achiral parent THIQ 6-O-sulfamate derivative 10 was successfully cocrystallized with the αβ-tubulin heterodimer. The derivative 10 binds at the colchicine site on tubulin, the first example of this compound class investigated in such detail, with its sulfamate group interacting with residues beyond the reach of colchicine itself, similar to a recently reported quinazolinone sulfamate derivative, 6a. The structure also suggests that for racemic C3-methyl-substituted THIQ derivatives, such as 8c, the (S)-enantiomer is likely to be preferentially accommodated within the colchicine site for steric reasons. The results further confirm the potential of nonsteroidal THIQ sulfamate derivatives for oncology and suggest that the mechanism of microtubule destabilization for the THIQ compound class is to prevent the curved-to-straight conformational transition of tubulin required for polymerization.

Enantioselective synthesis of tetrahydroisoquinoline derivatives via chiral-at-metal rhodium complex catalyzed [3+2] cycloaddition.

An asymmetric [3+2] cycloaddition of C,N-cyclic azomethine imines with α,β-unsaturated 2-acyl imidazoles catalyzed by a chiral-at-metal rhodium complex has been developed. The corresponding C-1-substituted tetrahydroisoquinoline derivatives were obtained in high yields (>90%) with excellent stereoselectivities (up to 99% ee and >20 : 1 dr). The reaction can be conducted on a gram-scale using a low catalyst loading (0.5 mol%) with high yield and selectivity.

A rhodium-catalysed three-component reaction to access C1-substituted tetrahydroisoquinolines.

A rhodium-catalyzed three-component reaction of diazo compounds, anilines and C,N-cyclic azomethine imines via trapping of transient ammonium ylides was developed. This reaction provided a simple and convenient approach for the synthesis of pharmaceutically intriguing tetrahydroisoquinoline derivatives in moderate to good yields (36-85%) with good diastereoselectivities (up to 95 : 5 dr) under mild reaction conditions.

Design, Biological Evaluation, and Molecular Modeling of Tetrahydroisoquinoline Derivatives: Discovery of A Potent P-Glycoprotein Ligand Overcoming Multidrug Resistance in Cancer Stem Cells.

P-Glycoprotein is a well-known membrane transporter responsible for the efflux of an ample spectrum of anticancer drugs. Its relevance in the management of cancer chemotherapy is increased in view of its high expression in cancer stem cells, a population of cancer cells with strong tumor-promoting ability. In the present study, a series of compounds were synthesized through structure modulation of [4'-(6,7-dimethoxy-3,4-dihydro-1 H-isoquinolin-2-ylmethyl)biphenyl-4-ol] (MC70), modifying the phenolic group of the lead compound. Among them, compound 5b emerged for its activity against the transporter (EC50 = 15 nM) and was capable of restoring doxorubicin antiproliferative activity at nontoxic concentration. Its behavior was rationalized through a molecular modeling study consisting of a well-tempered metadynamics simulation, which allowed one to identify the most favorable binding pose, and of a subsequent molecular dynamics run, which indicated a peculiar effect of the compound on the motion pattern of the transporter.

Regioselective Radical Ring Closure of Tertiary Enamides to the Synthesis of Trifluoroethyl‐containing N‐Acyl Isoindoline and N‐Acyl Tetrahydroisoquinoline Derivatives

AbstractThe regioselectivity of radical addition and cyclization reaction of tertiary enamides between 5‐membered benzoyl group and 5/6/7‐membered benzyl group ring closure was investigated, and trifluoroethyl ‐containing N‐Acyl isoindolines, N‐acyl tetrahydro‐isoquinolines, and N‐benzoyl tetrahydro‐1H‐benzo[c]azepine were obtained in moderate to good yields with high atom economy. Possible reaction pathway for the formation of the products was also discussed in this paper.magnified image

Synthesis and dopaminergic activity of a series of new 1-aryl tetrahydroisoquinolines and 2-substituted 1-aryl-3-tetrahydrobenzazepines

A series of new 1-aryl-6,7-dihydroxy tetrahydroisoquinolines with several substitution patterns in the 1-aryl group at C-1 were prepared in good yields. The influence of each substituent on the affinity and selectivity for D1 and D2 dopaminergic receptors was studied. Moreover, N-alkyl salts of these tetrahydroisoquinolines were used as starting material to synthesize a series of new 1-aryl-7,8-dihydroxy 3-tetrahydrobenzazepines derivatives with electron-withdrawing substituents at C-2 position by the diastereoselective Stevens rearrangement. The structure-activity relationship of these compounds was explored to evaluate the effect of the functional group at C-2 in benzazepines and the modification in the aryl group at the isoquinoline C-1 position towards the affinity and selectivity for the mentioned receptors. The 1-aryl-6,7-dihydroxy tetrahydroisoquinoline 4c shows significant affinity towards D2 receptor, with Ki value of 31 nM. This significant affinity can be attributed to the presence of a thiomethyl group, and it is the most active 1-aryl-6,7-dihydroxy tetrahydroisoquinoline derivative reported to date.

New Tetrahydroisoquinoline Derivatives Overcome Pgp Activity in Brain-Blood Barrier and Glioblastoma Multiforme in Vitro.

P-glycoprotein (Pgp) determines resistance to a broad spectrum of drugs used against glioblastoma multiforme (GB). Indeed, Pgp is highly expressed in GB stem cells and in the brain-blood barrier (BBB), the peculiar endothelium surrounding the brain. Inhibiting Pgp activity in the BBB and GB is still an open challenge. Here, we tested the efficacy of a small library of tetrahydroisoquinoline derivatives with an EC50 for Pgp ≤ 50 nM, in primary human BBB cells and in patient-derived GB samples, from which we isolated differentiated/adherent cells (AC, i.e., Pgp-negative/doxorubicin-sensitive cells) and stem cells (neurospheres, NS, i.e., Pgp-positive/doxorubicin-resistant cells). Three compounds used at 1 nM increased the delivery of doxorubicin, a typical substrate of Pgp, across BBB monolayer, without altering the expression and activity of other transporters. The compounds increased the drug accumulation within NS, restoring doxorubicin-induced necrosis and apoptosis, and reducing cell viability. In co-culture systems, the compounds added to the luminal face of BBB increased the delivery of doxorubicin to NS growing under BBB and rescued the drug’s cytotoxicity. Our work identified new ligands of Pgp active at low nanomolar concentrations. These compounds reduce Pgp activity in BBB and GB and improve in vitro chemotherapy efficacy in this tumor.

Tetrahydroquinoline and tetrahydroisoquinoline derivatives as potential selective PDE4B inhibitors

Tetrahydroquinoline and tetrahydroisoquinoline derivatives containing 2-phenyl-5-furan moiety were designed and synthesized as phosphodiesterase type 4 (PDE4) inhibitors. The bioassay results showed that title compounds showed good inhibitory activity against PDE4B and blockade of LPS (lipopolysaccharide) induced TNF-α release, which also exhibited considerable in vivo activity in animal models of asthma/COPD (chronic obstructive pulmonary disease) and sepsis induced by LPS. The bioactivity of compounds containing tetrahydroquinoline (series 4) was higher than that of tetrahydroisoquinoline derivatives (series 3). Compound 4 m with 4-methoxybenzene moiety exhibited the best potential selective activity against PDE4B. The primary structure–activity relationship study and docking results showed that the tetrahydroquinoline moiety of compound 4 m played a key role to form hydrogen bonds and π-π stacking interaction with PDE4B protein while the rest part of the molecule extended into the catalytic domain to block the access of cAMP and formed the foundation for inhibition of PDE4B. Based on LPS induced sepsis model for the measurement of TNF-α inhibition in Swiss Albino mice and neutrophilia inhibition for asthma and COPD in Sprague Dawley rats with the potential molecules, compound 4 m would be great promise as a hit inhibitor in the future study.

Discovery of N-Alkyl Piperazine Side Chain Based CXCR4 Antagonists with Improved Drug-like Properties.

A novel series of CXCR4 antagonists with piperidinyl and piperazinyl alkylamine side chains designed as butyl amine replacements are described. Several of these compounds showed similar activity to the parent compound TIQ-15 (5) in a SDF-1 induced calcium flux assay. Preliminary structure-activity relationship investigations led us to identify a series containing N-propyl piperazine side chain analogs exemplified by 16 with improved off-target effects as measured in a muscarinic acetylcholine receptor (mAChR) calcium flux assay and in a limited drug safety panel screen. Further efforts to explore SAR and optimize drug properties led to the identification of the N'-ethyl-N-propyl-piperazine tetrahydroisoquinoline derivative 44 and the N-propyl-piperazine benzimidazole compound 37, which gave the best overall profiles with no mAChR or CYP450 inhibition, good permeability in PAMPA assays, and metabolic stability in human liver microsomes.

Design, synthesis and biological evaluation of novel tetrahydroisoquinoline derivatives as P-glycoprotein-mediated multidrug resistance inhibitors

Multidrug resistance (MDR) is one of the main obstacles of clinical chemotherapy. A great deal of research shows that the occurrence of drug resistance in various malignant tumors is closely related to the expression of P-glycoprotein (P-gp) on the surface of the cell membrane. In this paper, based on the structure-activity relationship of phenylethyl tetrahydroisoquinoline, we choose tariquidar as the lead compound for the design and synthesis of 17 novel tetrahydroisoquinoline P-gp inhibitors. Additionally, in vitro and in vivo cytotoxicity assays and reversed MDR activity assays were evaluated. Among them, compound 3 had a good reversal of MDR activity and the reversal mechanism study of it was carried out. All of these results demonstrated that compound 3 was considered to be a promising P-gp-mediated MDR reversal candidate.

Dual-Excitation Polyoxometalate-Based Frameworks for One-Pot Light-Driven Hydrogen Evolution and Oxidative Dehydrogenation.

Dehydrogenation of the tetrahydroisoquinoline derivatives coupled with hydrogen production is important for hydrogen storage applications. Herein, we formulated a new system that embedded Dawson-type polyoxometalates as efficient photosensitizers into the pores of redox-active coordination polymers for the light-driven photocatalytic oxidative Mannich reaction and hydrogen evolution. In the designed Co-POM polymer, UV light excitation gives the excited state of the Dawson-type polyoxometalate first to oxidize electron donors or substrates; the reduced form (i.e., heteropolyblue) adsorbs visible light to achieve a new excited state, which reduced the cobalt redox sites and facilitates hydrogen evolution reaction. The photosensitizer recovered to the ground state, completing the catalytic cycle. Under the optimized conditions, Co-POM enabled the hydrogen evolution and dehydrogenation of tetrahydroisoquinoline without the presence of any other additives. The high catalytic efficiency and robustness indicated the advantages of the combining functional polyoxometalate-based catalysts and porous characters of the coordination polymers for the development of highly active heterogeneous catalysts.