Tetrahydroisoquinoline Research Articles

A Modular Approach for Diversity‐Oriented Synthesis of 1,3‐trans‐Disubstituted Tetrahydroisoquinolines: Seven‐Step Asymmetric Synthesis of Michellamines B and C

Abstract1,3‐trans‐Disubstituted tetrahydroisoquinoline (THIQ) is a common heterocyclic structural unit of naphthylisoquinoline alkaloids. The assembly of this structural unit is not trivial, which constitutes a substantial challenge in the total synthesis of naphthylisoquinoline alkaloids and related pharmaceuticals. Herein, we report a modular and convergent method for the rapid assembly of 1,3‐trans‐disubstituted THIQ frameworks through a three‐component Catellani reaction and a AuI‐catalyzed cyclization/reduction cascade. With widely available simple aryl iodides, aziridines and (triisopropylsilyl)acetylene as the building blocks, this method paves a practical way for the diversity‐oriented synthesis of 1,3‐trans‐disubstituted THIQs. Based on this new method, concise syntheses of an analogue of the new drug mevidalen and four naphthylisoquinoline alkaloids have been accomplished, demonstrating the broad synthetic utility of this approach.

Cell Fate following Irradiation of MDA-MB-231 and MCF-7 Breast Cancer Cells Pre-Exposed to the Tetrahydroisoquinoline Sulfamate Microtubule Disruptor STX3451.

A tetrahydroisoquinoline (THIQ) core is able to mimic the A and B rings of 2-methoxyestradiol (2ME2), an endogenous estrogen metabolite that demonstrates promising anticancer properties primarily by disrupting microtubule dynamic instability parameters, but has very poor pharmaceutical properties that can be improved by sulfamoylation. The non-steroidal THIQ-based microtubule disruptor 2-(3-bromo-4,5-dimethoxybenzyl)-7-methoxy-6-sulfamoyloxy-1,2,3,4-tetrahydroisoquinoline (STX3451), with enhanced pharmacokinetic and pharmacodynamic profiles, was explored for the first time in radiation biology. We investigated whether 24 h pre-treatment with STX3451 could pre-sensitize MCF-7 and MDA-MB-231 breast cancer cells to radiation. This regimen showed a clear increase in cytotoxicity compared to the individual modalities, results that were contiguous in spectrophotometric analysis, flow cytometric quantification of apoptosis induction, clonogenic studies and microscopy techniques. Drug pre-treatment increased radiation-induced DNA damage, with statistically more double-strand (ds) DNA breaks demonstrated. The latter could be due to the induction of a radiation-sensitive metaphase block or the increased levels of reactive oxygen species, both evident after compound exposure. STX3451 pre-exposure may also delay DNA repair mechanisms, as the DNA damage response element ataxia telangiectasia mutated (ATM) was depressed. These in vitro findings may translate into in vivo models, with the ultimate aim of reducing both radiation and drug doses for maximal clinical effect with minimal adverse effects.

Photosensitized selective semi-oxidation of tetrahydroisoquinoline: a singlet oxygen path.

Selective semi-oxidation of tetrahydroisoquinoline (THIQ) leads to a valuable dihydroisoquinoline (DHIQ) derivative via singlet oxygen photooxidation process. Typical photosensitisers (i.e., Ru complexes) can activate the reaction even under heterogeneous conditions that facilitate catalyst separation and reusability. In contrast to DHIQ, THIQ acts as an efficient singlet oxygen quencher driving the reaction selectivity. The reaction can also be facilitated by semiconductor catalysts such as MoCo@GW, a glass wool-based catalyst that is easy to separate and reuse and compatible with flow photochemistry. Its role is to mediate the formation of isoquinoline (IQ) and thus an in situ-generated singlet oxygen catalyst. Laser flash photolysis with NIR detection provides proof of the singlet oxygen mechanism proposed and rate constants for the key steps that mediate the oxidation.

Brown Seaweed‐Derived Alginic Acid: An Efficient and Reusable Catalyst for Pictet‐Spengler Reaction to Access Tetrahydro‐β‐Carboline and Tetrahydroisoquinoline Frameworks

AbstractPictet‐Spengler reaction (PSR) is an efficient and reliable synthetic tool for the construction of tetrahydro‐β‐carbolines (THBCs) and tetrahydroisoquinolines (THIQs) moieties. Herein, we reported a brown seaweed‐derived biocompatible alginic acid as an alternative and effective reusable catalyst for PSR. This protocol was found suitable for various aliphatic and aromatic aldehydes with electron‐donating and withdrawing groups resulting in good to excellent yields. The utility of this sustainable protocol highlighted by synthesizing different THBCs and THIQs including a natural spirooxindole (±)‐coerulescine (9a) and its derivative 9b. The reusability of catalyst was also examined, and no significant deterioration in the reaction yields was observed till the 6th cycle.

Reductive inactivation of the hemiaminal pharmacophore for resistance against tetrahydroisoquinoline antibiotics

Antibiotic resistance is becoming one of the major crises, among which hydrolysis reaction is widely employed by bacteria to destroy the reactive pharmacophore. Correspondingly, antibiotic producer has canonically co-evolved this approach with the biosynthetic capability for self-resistance. Here we discover a self-defense strategy featuring with reductive inactivation of hemiaminal pharmacophore by short-chain dehydrogenases/reductases (SDRs) NapW and homW, which are integrated with the naphthyridinomycin biosynthetic pathway. We determine the crystal structure of NapW·NADPH complex and propose a catalytic mechanism by molecular dynamics simulation analysis. Additionally, a similar detoxification strategy is identified in the biosynthesis of saframycin A, another member of tetrahydroisoquinoline (THIQ) antibiotics. Remarkably, similar SDRs are widely spread in bacteria and able to inactive other THIQ members including the clinical anticancer drug, ET-743. These findings not only fill in the missing intracellular events of temporal-spatial shielding mode for cryptic self-resistance during THIQs biosynthesis, but also exhibit a sophisticated damage-control in secondary metabolism and general immunity toward this family of antibiotics.

The Photocatalyst-Free Cross-Dehydrogenative Coupling Reaction Enabled by Visible-Light Direct Excitation of Substrate.

A new photocatalyst-free strategy for the cross-dehydrogenative C-C and C-P coupling reaction has been described. This protocol provides a concise method to synthesize various 1-substituted tetrahydroisoquinoline (THIQ) derivatives enabled by visible-light direct excitation of substrates without using any photocatalyst. Moreover, a wide substrate scope demonstrated good synthetic versatility and practicality.

Development of novel tetrahydroisoquinoline-hydroxamate conjugates as potent dual SERDs/HDAC inhibitors for the treatment of breast cancer

Concomitant inhibition of estrogen receptor alpha (ERα) and histone deacetylase (HDAC) signaling has been proven effective in endocrine-resistant ER+ breast cancers. Herein, a series of tetrahydroisoquinoline (THIQ)-hydroxamate conjugates were rationally designed and synthesized as dual SERDs/HDAC inhibitors by incorporating the hydroxamate, a known HDAC pharmacophore, into a privileged THIQ scaffold of selective ERα degraders (SERDs). Some of these THIQ-hydroxamate conjugates displayed remarkable HDAC6 inhibition and improved antiproliferative activity against MCF-7 cells. Particularly, the most potent HDAC inhibitor 19k also exhibits potent ERα binding affinity, good ERα degradation efficacy and the best antiproliferative activity. Besides, 19k displayed superior antitumor efficacy than the drug combination (Fulvestrant + SAHA) through promoting ERα degradation and histone acetylation in an MCF-7 xenograft model, without causing observable toxicity. Collectively, this study validates the therapeutic potential of a dual-acting compound with potent ERα degradation efficacy and HDAC6 inhibition in breast cancer.

Iridium‐Catalyzed Enantioselective Hydrogenation of 3‐Substituted Isoquinolinium Salts

AbstractChiral tetrahydroisoquinolines (THIQ) is a highly important molecular skeleton in natural alkaloids and biologically active compounds, and its derivatives are often used as key intermediates for the synthesis of drugs. Herein, we described an efficient enantioselective hydrogenation of 3‐substituted isoquinolinium salts catalyzed by a bromine‐bridged dimeric complex [{Ir(H)[(R,S,Sax)‐Ph‐ax‐Josiphos]}2(μ‐Br)3]+Br−. This efficient enantioselective transformation could provide a series of useful chiral cyclic amines, which were of great potential value in natural product modification and drug molecular preparation in high yields and moderate to excellent enantioselectivities (68–97% ee). Additionally, turnover number experiments and a gram‐scale synthesis of chiral 3‐phenyltetrahydroisoquinoline were conducted.

Multienzyme One-Pot Cascades Incorporating Methyltransferases for the Strategic Diversification of Tetrahydroisoquinoline Alkaloids.

The tetrahydroisoquinoline (THIQ) ring system is present in a large variety of structurally diverse natural products exhibiting a wide range of biological activities. Routes to mimic the biosynthetic pathways to such alkaloids, by building cascade reactions in vitro, represents a successful strategy and can offer better stereoselectivities than traditional synthetic methods. S‐Adenosylmethionine (SAM)‐dependent methyltransferases are crucial in the biosynthesis and diversification of THIQs; however, their application is often limited in vitro by the high cost of SAM and low substrate scope. In this study, we describe the use of methyltransferases in vitro in multi‐enzyme cascades, including for the generation of SAM in situ. Up to seven enzymes were used for the regioselective diversification of natural and non‐natural THIQs on an enzymatic preparative scale. Regioselectivites of the methyltransferases were dependent on the group at C‐1 and presence of fluorine in the THIQs. An interesting dual activity was also discovered for the catechol methyltransferases used, which were found to be able to regioselectively methylate two different catechols in a single molecule.

Multienzyme One-Pot Cascades Incorporating Methyltransferases for the Strategic Diversification of Tetrahydroisoquinoline Alkaloids.

The tetrahydroisoquinoline (THIQ) ring system is present in a large variety of structurally diverse natural products exhibiting a wide range of biological activities. Routes to mimic the biosynthetic pathways to such alkaloids, by building cascade reactions in vitro, represents a successful strategy and can offer better stereoselectivities than traditional synthetic methods. S-Adenosylmethionine (SAM)-dependent methyltransferases are crucial in the biosynthesis and diversification of THIQs; however, their application is often limited in vitro by the high cost of SAM and low substrate scope. In this study, we describe the use of methyltransferases in vitro in multi-enzyme cascades, including for the generation of SAM in situ. Up to seven enzymes were used for the regioselective diversification of natural and non-natural THIQs on an enzymatic preparative scale. Regioselectivites of the methyltransferases were dependent on the group at C-1 and presence of fluorine in the THIQs. An interesting dual activity was also discovered for the catechol methyltransferases used, which were found to be able to regioselectively methylate two different catechols in a single molecule.

The Alkaloids from Lophophora diffusa and Other "False Peyotes".

Commonly, false peyote refers to Lophophora diffusa. However, several other unrelated cacti go by this colloquial name. They either resemble "true" peyote, Lophophora williamsii, or are found in similar habitats. To date, over 40 different alkaloids have been isolated from the Lophophora genus. Of these, only the pharmacological actions of mescaline (1) have been extensively investigated. The major alkaloid in L. diffusa is pellotine (2), a tetrahydroisoquinoline (THIQ), which was briefly marketed as a sleeping aid around the beginning of the 20th century, following reports of its hypnotic properties in humans. Pharmacological experiments with the Lophophora THIQs were performed at the turn of the 20th century, whereas the chemical synthesis was not realized until several decades later. The biosynthetic pathways of the main Lophophora alkaloids were reported at the end of the 1960s. In this review, the relationship of the different "false peyotes" to L. williamsii, in regard to their alkaloid content, the bio- and chemical synthesis of the most relevant alkaloids, and their corresponding pharmacology will be outlined and discussed.

Accelerating H2 Evolution by Anodic Semi-dehydrogenation of Tetrahydroisoquinolines in Water over Co3 O4 Nanoribbon Arrays Decorated Nickel Foam.

Coupling the H2 evolution reaction in water with thermodynamically favorable organic oxidation reactions is highly desirable, because it can enhance the energy conversion efficiency compared with electrocatalytic water splitting, and produce value-added chemicals instead of O2 in the anodic reaction. Herein, Co3 O4 nanoribbon arrays in situ grown on nickel foam (Co3 O4 @NF) was employed as an effective electrocatalyst for the selective oxidation of tetrahydroisoquinolines (THIQs). Various value-added semi-dehydrogenation products including dihydroisoquinolines with electro-deficient or -rich groups could be obtained with moderate yields and faradaic efficiencies. Benefitting from the rich surface active sites of Co3 O4 @NF, a two-electrode (Co3 O4 @NF||Pt) electrolytic system drove a benchmark current density of 10 mA cm-2 at a cell voltage as low as 1.446 V in 1.0 M KOH aqueous solution containing 0.02 M THIQ, which was reduced by 174 mV in comparison with that of overall water splitting.

Genome-Directed Discovery of Tetrahydroisoquinolines from Deep-Sea Derived Streptomyces niveus SCSIO 3406.

A genome-directed discovery strategy to identify new tetrahydroisoquinolines (THIQs) was applied to deep-sea derived Streptomyces niveus SCSIO 3406; 11 THIQs were found representing three THIQ classes. Known aclidinomycins A (1) and B (2) were isolated along with nine new compounds, aclidinomycins C-K (3-11). The structures were elucidated using extensive spectroscopic analyses and single-crystal X-ray diffraction methods. The core skeleton of compounds 6-9 contains a fused tetrahydropyran (THP) as an integral part of a distinct type of 6/6/6/6/5/5 polycyclic motif. This is the first report of such a system. Beyond their discovery, we also report here a proposed biosynthetic route to these interesting natural products as well as a preliminary survey of their antimicrobial activities.

Medicinal chemistry perspectives of 1,2,3,4-tetrahydroisoquinoline analogs - biological activities and SAR studies.

Isoquinoline alkaloids are a large group of natural products in which 1,2,3,4-tetrahydroisoquinolines (THIQ) form an important class. THIQ based natural and synthetic compounds exert diverse biological activities against various infective pathogens and neurodegenerative disorders. Due to these reasons, the THIQ heterocyclic scaffold has garnered a lot of attention in the scientific community which has resulted in the development of novel THIQ analogs with potent biological activity. The present review provides a much-needed update on the biological potential of THIQ analogs, their structural–activity relationship (SAR), and their mechanism of action. In addition, a note on commonly used synthetic strategies for constructing the core scaffold has also been discussed.

Altered urinary tetrahydroisoquinoline derivatives in patients with Tourette syndrome: reflection of dopaminergic hyperactivity?

Tetrahydroisoquinolines (TIQs) such as salsolinol (SAL), norsalsolinol (NSAL) and their methylated derivatives N-methyl-norsalsolinol (NMNSAL) and N-methyl-salsolinol (NMSAL), modulate dopaminergic neurotransmission and metabolism in the central nervous system. Dopaminergic neurotransmission is thought to play an important role in the pathophysiology of chronic tic disorders, such as Tourette syndrome (TS). Therefore, the urinary concentrations of these TIQ derivatives were measured in patients with TS and patients with comorbid attention-deficit/hyperactivity disorder (TS + ADHD) compared with controls. Seventeen patients with TS, 12 with TS and ADHD, and 19 age-matched healthy controls with no medication took part in this study. Free levels of NSAL, NMNSAL, SAL, and NMSAL in urine were measured by a two-phase chromatographic approach. Furthermore, individual TIQ concentrations in TS patients were used in receiver-operating characteristics (ROC) curve analysis to examine the diagnostic value. NSAL concentrations were elevated significantly in TS [434.67 ± 55.4 nmol/l (standard error of mean = S.E.M.), two-way ANOVA, p < 0.0001] and TS + ADHD patients [605.18 ± 170.21 nmol/l (S.E.M.), two-way ANOVA, p < 0.0001] compared with controls [107.02 ± 33.18 nmol/l (S.E.M.), two-way ANOVA, p < 0.0001] and NSAL levels in TS + ADHD patients were elevated significantly in comparison with TS patients (two-way ANOVA, p = 0.017). NSAL demonstrated an AUC of 0.93 ± 0.046 (S.E.M) the highest diagnostic value of all metabolites for the diagnosis of TS. Our results suggest a dopaminergic hyperactivity underlying the pathophysiology of TS and ADHD. In addition, NSAL concentrations in urine may be a potential diagnostic biomarker of TS.

SAR Matrices Enable Discovery of Mixed Efficacy μ-Opioid Receptor Agonist Peptidomimetics with Simplified Structures through an Aromatic-Amine Pharmacophore.

We previously described the development of potent μ-opioid receptor (MOR)-agonist/δ-opioid receptor (DOR)-antagonist peptidomimetic ligands as an approach toward effective analgesics with reduced side effects. In this series, a tetrahydroquinoline (THQ) or substituted phenyl is employed to link two key pharmacophore elements, a dimethyltyrosine amino acid and typically an aromatic pendant. Using new and previously reported analogues, we constructed a structure-activity relationship (SAR) matrix that probes the utility of previously reported amine pendants. This matrix reveals that the MOR-agonist/DOR-antagonist properties of these ligands do not change when a tetrahydroisoquinoline (THIQ) pendant is used, despite removal of substituents on the core phenyl ring. Based on this observation, we retained the THIQ pendant and replaced the phenyl core with simpler aliphatic chain structures. These simpler analogues proved to be potent MOR-agonists with high variability in their effects at the DOR and the κ-opioid receptor (KOR). These data show that the amine of the THIQ pendant may be a novel pharmacophore element that favors high MOR-efficacy, whereas the aromatic ring of the THIQ pendant may produce high MOR-potency. Combined, the two pharmacophores within the THIQ pendant may be a structurally efficient means of converting opioid peptides and peptidomimetics into potent and efficacious MOR-agonists.

One-Step Synthesis of THIQ via a Catellani Strategy

Tetrahydroisoquinoline (THIQ), an important heterocyclic scaffold, is prevalent in bioactive natural products and therapeutic agents. Growing efforts have been devoted to the efficient preparation of this valuable scaffold. However, current strategies usually rely on specially functionalized complex substrates. Recently, our group developed a modular one-step three-component synthesis of THIQs via a Catellani/Heck/aza-Michael cascade, using simple aryl iodides, aziridines, and olefins as the starting materials.

Photo-induced sp3 C-H bond arylation, cyanation and nitroalkylation of tetrahydroisoquinolines (THIQs) under visible light irradiation using a combination of NHPI and Rose Bengal.

This work reports a sustainable protocol for α-arylation of tetrahydroisoquinolines (THIQs) with aryl diazonium salts using a combination of a cheap and stable oxidant, N-hydroxyphthalimide (NHPI), and an inexpensive dye photosensitizer, Rose Bengal (RB), for the first time. The reaction was performed at ambient temperature using green LED light irradiation under an oxygen atmosphere. The developed α-arylation protocol shows a diverse substrate scope for various THIQs and aryl diazonium salts. The work also explores nitroalkylation and cyanation under the developed reaction conditions. A possible SET mechanism is involved which was confirmed by ESI-MS analysis of the reaction mixture.

Metal‐Free Multicomponent Construction of Tetrahydroisoquinoline‐Indole Derivatives via In Situ Generated ortho‐Quinonoid Intermediate

AbstractA metal‐ and ligand‐free multicomponent coupling of tetrahydroisoquinoline (THIQ), ortho‐hydroxybenzaldehydes and indoles under solvent‐free conditions is described. The developed protocol provided a waste‐free and concise access to C(1)‐functionalized THIQ‐indole derivatives under green conditions. The reactant molar ratio and neutral conditions were found crucial for controlling the selectivity of desired THIQ‐indole product over competitive by‐products i. e. oxazine and bis(indolyl)methane. The experimental and DFT study revealed the involvement of ortho‐quinonoid species which reacts with indoles in situ to form THIQ‐indole derivatives.

The A3 Redox-Neutral C1-Alkynylation of Tetrahydroisoquinolines: A Comparative Study between Visible Light Photocatalysis and Transition-Metal Catalysis

AbstractConsidering the current challenges of the A3 redox-neutral C1-alkynylation of tetrahydroisoquinolines (THIQs), we studied this synthetic tool under visible light photocatalysis and transition-metal catalysis in order to describe alternative reaction conditions and discuss possible improvements to this process. We demonstrated that 1-alkynylated THIQs can be readily obtained by three different approaches: iridium-based photocatalysis and copper ([CuBr(PPh3)3]) and silver (AgNO3) catalysis under mild, selective and accessible reaction conditions. Among these approaches, the copper(I)-based methodology resulted in the most robust, optimal reaction conditions for the synthesis of a series of 18 1-alkynylated THIQs in moderate to excellent yields and with high selectivity for the endo-alkynylated products. Moreover, this reaction can be accelerated by microwave irradiation (120 °C, 15 min) affording a novel library of diverse THIQs with alkyne and N-substituent moieties, from unreactive and uncommon substrates, that could be further transformed into new compounds of interest.