New tetrahydroisoquinoline-4-carbonitrile derivatives as potent agents against cyclin-dependent kinases, crystal structures, and computational studies.

The synthesis of two new hexahydroisoquinoline-4-carbonitrile derivatives (3a and 3b) is reported along with spectroscopic data and their crystal structures. In compound 3a, the intramolecular O-H···O hydrogen bond constraints the acetyl and hydroxyl groups to be syn. In the crystal, inversion dimers are generated by C-H···O hydrogen bonds and are connected into layers parallel to (10-1) by additional C-H···O hydrogen bonds. The layers are stacked with Cl···S contacts 0.17 Å less than the sum of the respective van der Waals radii. The conformation of the compound 3b is partially determined by the intramolecular O-H···O hydrogen bond. A puckering analysis of the tetrahydroisoquinoline unit was performed. In the crystal, O-H···O and C-H···O hydrogen bonds together with C-H···π(ring) interactions form layers parallel to (01-1) which pack with normal van der Waals interactions. To understand the binding efficiency and stability of the title molecules, molecular docking, and 100 ns dynamic simulation analyses were performed with CDK5A1. To rationalize their structure-activity relationship(s), a DFT study at the B3LYP/6-311++G** theoretical level was also done. The 3D Hirshfled surfaces were also taken to investigate the crystal packings of both compounds. In addition, their ADMET properties were explored.Communicated by Ramaswamy H. Sarma.

Recent advances in the synthesis and activity of analogues of bistetrahydroisoquinoline alkaloids as antitumor agents.

Ecteinascidin 743 (Et-743), also known by the trade name Yondelis®, is the pioneering marine natural product to be successfully developed as an antitumor drug. Moreover, it is the first tetrahydroisoquinoline natural product used clinically for antitumor therapy since Kluepfel, a Canadian scientist, discovered the tetrahydroisoquinoline alkaloid (THIQ) naphthyridinomycin in 1974. Currently, almost a hundred natural products of bistetrahydroisoquinoline type have been reported. Majority of these bistetrahydroisoquinoline alkaloids exhibit diverse pharmacological activities, with some family members portraying potent antitumor activities such as Ecteinascidins, Renieramycins, Saframycins, Jorumycins, among others. Due to the unique chemical structure and exceptional biological activity of these natural alkaloids, coupled with their scarcity in nature, research seeking to provide material basis for further bioactivity research through total synthesis and obtaining compound leads with medicinal value through structural modification, remains a hot topic in the field of antitumor drug R&D. Despite the numerous reviews on the total synthesis of bistetrahydroisoquinoline natural products, comprehensive reviews on their structural modification are apparently scarce. Moreover, structural modification of bioactive natural products to acquire lead compounds with improved pharmaceutical characteristics, is a crucial approach for innovative drug discovery. This paper presents an up-to-date review of both structural modification and activity of bistetrahydroisoquinoline natural products. It highlights how such alkaloids can be used as antitumor lead compounds through careful chemical modifications. This review offers valuable scientific references for pharmaceutical chemists engaged in developing novel antitumor agents based on such alkaloid modifications, as well as those with such a goal in future.

Design, synthesis, and biological evaluation of simplified tetrahydroisoquinoline analogs.

A series of tetrahydroisoquinoline derivatives were prepared and their antitumor activity was studied against several human carcinoma cell lines, including Ketr3, BEL-7402, BGC-823, KB, HCT-8, MCF-7, HeLa, A2780, A549, and HT-1080. Compound 20, an analog of phthalascidin 650, exhibited good broad-spectrum antitumor activity in vitro. However, compounds 19 and 21, in which the side chains at C-22 are simplified, showed no obvious antitumor activity, indicating that the C-22 side chain of this type of compound has a greater impact on its activity. The difference in the in vivo activity between compound 20 and phthalascidin 650 also shows a significant effect of the substituents on the skeleton structure on the in vivo activity.

Recent Advances in the Total Synthesis of the Tetrahydroisoquinoline Alkaloids (2002-2020).

The tetrahydroisoquinoline (THIQ) natural products constitute one of the largest families of alkaloids and exhibit a wide range of structural diversity and biological activity. Ranging from simple THIQ natural products to complex trisTHIQ alkaloids such as the ecteinascidins, the chemical syntheses of these alkaloids and their analogs have been thoroughly investigated due to their intricate structural features and functionalities, as well as their high therapeutic potential. This review describes the general structure and biosynthesis of each family of THIQ alkaloids as well as recent advancements of the total synthesis of these natural products from 2002 to 2020. Recent chemical syntheses that have emerged harnessing novel, creative synthetic design, and modern chemical methodology will be highlighted. This review will hopefully serve as a guide for the unique strategies and tools used in the total synthesis of THIQ alkaloids, as well as address the longstanding challenges in their chemical and biosynthesis.

Progress in the Total Synthesis of Antitumor Tetrahydroisoquinoline Alkaloids.

Among the tetrahydroisoquinoline(THIQ) of natural products, a family of THIQ alkaloids has the characteristics of similar biosynthetic pathway. Such THIQ alkaloids family mainly include Renieramycins, Ecteinasicdins, Tetrazaomine, Lemonomycin, etc. Most of these natural compounds have strong antitumor activities, and its family member Ecteinasicdins743 (ET-743, Trabectedin) has been marketed in the European Union and the United States for the treatment of advanced soft tissue tumors and ovarian cancer. Because of the excellent biological activity and complex chemical structure of this kind of THIQ products, it has aroused great interest of biologists and chemists, and many synthetic chemists have paid considerable efforts to their total synthesis over the past decade. Based on this, the recent advances in the total synthesis of such THIQ alkaloids are reviewed.

Evaluation of the Local Anesthetic Activity, Acute Toxicity, and Structure-Toxicity Relationship in Series of Synthesized 1-Aryltetrahydroisoquinoline Alkaloid Derivatives In Vivo and In Silico.

Isoquinoline alkaloids constitute one of the most common classes of alkaloids that have shown a pronounced role in curing various diseases. Finding ways to reduce the toxicity of these molecules and to increase their therapeutic margin is an urgent matter. Here, a one-step method for the synthesis of a series of 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines was performed in 85-98% yield by the Pictet-Spengler reaction. This was accomplished using the reaction between 3,4-dimethoxyphenylethylamine and substituted benzaldehydes boiling in trifluoroacetic acid. Furthermore, 1-(3'-amino-, 4'-aminophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines were obtained in 94% and 97% yield by reduction in 1-(3'-nitro-, 4'-nitrophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines with SnCl2 × 2H2O. The structures of the substances obtained were confirmed by infrared (IR) and nuclear magnetic resonance (1H and 13C NMR) spectra. ADMET/TOPKAT in silico study concluded that the synthesized compounds exhibited acceptable pharmacodynamic and pharmacokinetic properties without carcinogenic or mutagenic potential but with variable hepatotoxicity. The acute toxicity and structure-toxicity relationship (STR) in the series of 20 derivatives of 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines (3a-r, 4a, b) was studied via determination of acute toxicity and resorptive action in white mice employing intragastric step-by-step administration. The first compound, 1-phenyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (3a), showed the highest toxicity with LD50 of 280 mg/kg in contrast to 1-(3'-bromo -4'-hydroxyphenyl)-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (3e) which proved to be the safest of the compounds studied. Its toxicity was 13.75 times lower than that of the parent compound 3a. All compounds investigated showed high local anesthetic activity on rabbit eyes in the concentrations studied. Only 3r, 3n, and 4a caused eye irritation and redness. All investigated derivatives (except 4b) in 1% concentration were more active than lidocaine, providing longer duration of complete anesthesia. Therefore, based on the obtained results of in silico tests, local anesthesia, and acute toxicity, a conclusion can be drawn that the experimental compounds need further extensive future investigations and possible modifications so that they can act as promising drug candidates.

Selective oxidative ß-C-H bond sulfenylation of tetrahydroisoquinolines with elemental sulfur.

In this article, a convenient and efficient KIO3-promoted oxidative sulfenylation at the ß-position of tetrahydroisoquinolines and subsequent aromatization in the presence of elemental S8 is presented. The reaction proceeds with moderate to good yields via a double C-S formation process. A wide range of structurally diverse 4-sulfenylisoquinolines/3-sulfenylpiperidine were synthesized with excellent functional group tolerance and high efficiency.

Simplified hybrids of two anticancer bistetrahydroisoquinoline alkaloids ecteinascidin 743 and cribrostatin 4 and inhibitory activity against proliferation of cancer cells.

Ecteinascidin 743 is a famous marine drug used in anticancer treatments. In this work, a series of simplified hybrids/analogues have been synthesized by employing a newly developed chemistry that integrates the partial structural features of two anticancer bis-tetrahydroisoquinoline alkaloids ecteinascidin 743 and cribrostatin 4. The described Suzuki-coupling protocol enabled us to easily introduce variable functionalities at the C3 position of the basic skeleton of bis-tetrahydroisoquinoline alkaloids for the first time. Cytotoxic examination showed that analogue 21f exhibited inhibitory activities with IC50 values in the low 10-6 M range against the proliferation of the cancer cell lines A549, HepG2, and MDA-MB-231. This work reveals that diversifying the C3/C4 olefin in the skeleton of tetrahydroisoquinoline alkaloids is a useful means to generate potential pharmaceuticals.

SbCl3 Initiated Aerobic Phosphorylation of sp3 C-H Bond: A Facile Approach to α-Phosphorylated Tetrahydroisoquinolines.

An aerobic phosphorylation of N-aryltetrahydroisoquinolines was realized by SbCl3 initiated sp3 C-H bond functionalization, providing a series of α-aminophosphonates in high yields. This work reveals that SbCl3 /O2 is an efficient and facile catalyst system to enable the aerobic C-H functionalization, and antimony containing reagents might be potentially applied to more general transformations.

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

1,3-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.

Iridium-Catalyzed Asymmetric Hydrogenation of 2,3-Diarylallyl Amines with a Threonine-Derived P-Stereogenic Ligand for the Synthesis of Tetrahydroquinolines and Tetrahydroisoquinolines.

Chiral compounds containing nitrogen heteroatoms are fundamental substances for the chemical, pharmaceutical and agrochemical industries. However, the preparation of some of these interesting scaffolds is still underdeveloped. Herein we present the synthesis of a family of P-stereogenic phosphinooxazoline iridium catalysts from L-threonine methyl ester and their use in the asymmetric hydrogenation of N-Boc-2,3-diarylallyl amines, achieving very high enantioselectivity. Furthermore, the synthetic utility of the 2,3-diarylpropyl amines obtained is demonstrated by their transformation to 3-aryl-tetrahydroquinolines and 4-benzyl-tetrahydroisoquinolines, which have not yet been obtained in an enantioselective manner by direct reduction of the corresponding aromatic heterocycles. This strategy allows the preparation of these types of alkaloids with the highest enantioselectivity reported up to date.

Screening of σ2 Receptor Ligands and In Vivo Evaluation of 11C-Labeled 6,7-Dimethoxy-2-[4-(4-methoxyphenyl)butan-2-yl]-1,2,3,4-tetrahydroisoquinoline for Potential Use as a σ2 Receptor Brain PET Tracer.

In this study, a panel of 46 compounds containing five different scaffolds known to have high σ2 receptor affinity were screened. 6,7-Dimethoxy-2-[4-(4-methoxyphenyl)butan-2-yl]-1,2,3,4-tetrahydroisoquinoline [(±)-7] (Ki for σ1 = 48.4 ± 7.7 nM, and Ki for σ2 = 0.59 ± 0.02 nM) and its desmethyl analogue, (±)-8 (Ki for σ1 = 108 ± 35 nM, and Ki for σ2 = 4.92 ± 0.59 nM), showed excellent binding affinity and subtype selectivity for σ2 receptors. In vitro cell binding indicated that σ2 receptor binding of [11C]-(±)-7 and [11C]-(±)-8 was dependent on TMEM97 protein expression. In PET studies, the peak brain uptake of [11C]-(±)-7 (8.28 ± 2.52%ID/cc) was higher than that of [11C]-(±)-8 (4.25 ± 0.97%ID/cc) with specific distribution in the cortex and hypothalamus. Brain uptake or tissue binding was selectively inhibited by ligands with different σ2 receptor binding affinities. The results suggest [11C]-(±)-7 can be used as a PET radiotracer for imaging the function of σ2 receptors in central nervous system disorders.

Advances in Sulfonamide Kappa Opioid Receptor Antagonists: Structural Refinement and Evaluation of CNS Clearance.

Focused modification of a sulfonamide-based kappa opioid receptor (KOR) antagonist series previously reported by this laboratory was investigated. A total of 32 analogues were prepared to explore linker replacement, constraint manipulation, and aryl group or amine substitution. All analogues were assayed for KOR antagonist activity, and the initial lead compound was assessed for in vivo CNS penetration. The most improved analogue possessed a 4-fold increase of potency (IC50 = 18.9 ± 4.4 nM) compared with the lead compound (IC50 = 83.5 ± 20 nM) from an earlier work. The initial lead compound was found to attain suitable brain levels and to possess a shorter clearance time than canonical KOR antagonists such as JDTic.

Synthesis and biological evaluation of tetrahydroisoquinoline-derived antibacterial compounds.

Antibiotic resistance is one of the greatest threats to modern medicine. Drugs that were once routinely used to treat infections are being rendered ineffective, increasing the demand for novel antibiotics with low potential for resistance. Here we report the synthesis of 18 novel cationic tetrahydroisoquinoline-triazole compounds. Five of the developed molecules were active against S. aureus at a low MIC of 2-4 µg/mL. Hit compound 4b was also found to eliminate M. tuberculosis H37Rv at MIC of 6 µg/mL. This potent molecule was found to eliminate S. aureus effectively, with no resistance observed after thirty days of sequential passaging. These results identified compound 4b and its analogues as potential candidates for further drug development that could help tackle the threat of antibiotic resistance.

Discovery and optimization of new 6, 7-dihydroxy-1, 2, 3, 4-tetrahydroisoquinoline derivatives as potent influenza virus PAN inhibitors.

Annual unpredictable efficacy of vaccines, coupled with emerging drug resistance, underlines the development of new antiviral drugs to treat influenza infections. The N-terminal domain of the PA (PAN) endonuclease is both highly conserved across influenza strains and serotypes and is indispensable for the viral lifecycle, making it an attractive target for new antiviral therapies. Here, we describe the discovery of a new class of PAN inhibitors derived from recently identified, highly active hits for PAN endonuclease inhibition. By use of structure-guided design and systematic SAR exploration, the hits were elaborated through a fragment growing strategy, giving rise to a series of 1, 3-cis-2-substituted-1-(3, 4-dihydroxybenzyl)-6, 7-dihydroxy-1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylic acid derivatives as potent PAN inhibitors. This approach ultimately resulted in the development of a new lead compound 13e, which exhibited an EC50 value of 4.50 µM against H1N1 influenza virus in MDCK cells.

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.

Complete biosynthesis of the bisbenzylisoquinoline alkaloids guattegaumerine and berbamunine in yeast.

Benzylisoquinoline alkaloids (BIAs) are a diverse class of medicinal plant natural products. Nearly 500 dimeric bisbenzylisoquinoline alkaloids (bisBIAs), produced by the coupling of two BIA monomers, have been characterized and display a range of pharmacological properties, including anti-inflammatory, antitumor, and antiarrhythmic activities. In recent years, microbial platforms have been engineered to produce several classes of BIAs, which are rare or difficult to obtain from natural plant hosts, including protoberberines, morphinans, and phthalideisoquinolines. However, the heterologous biosyntheses of bisBIAs have thus far been largely unexplored. Here, we describe the engineering of yeast strains that produce the Type I bisBIAs guattegaumerine and berbamunine de novo. Through strain engineering, protein engineering, and optimization of growth conditions, a 10,000-fold improvement in the production of guattegaumerine, the major bisBIA pathway product, was observed. By replacing the cytochrome P450 used in the final coupling reaction with a chimeric variant, the product profile was inverted to instead produce solely berbamunine. Our highest titer engineered yeast strains produced 108 and 25 mg/L of guattegaumerine and berbamunine, respectively. Finally, the inclusion of two additional putative BIA biosynthesis enzymes, SiCNMT2 and NnOMT5, into our bisBIA biosynthetic strains enabled the production of two derivatives of bisBIA pathway intermediates de novo: magnocurarine and armepavine. The de novo heterologous biosyntheses of bisBIAs presented here provide the foundation for the production of additional medicinal bisBIAs in yeast.

Oceanalin B, a Hybrid α,ω-Bifunctionalized Sphingoid Tetrahydroisoquinoline ß-Glycoside from the Marine Sponge Oceanapia sp.

Oceanalin B (1), an α,ω-bipolar natural product belonging to a rare family of sphingoid tetrahydoisoquinoline ß-glycosides, was isolated from the EtOH extract of the lyophilized marine sponge Oceanapia sp. as the second member of the series after oceanalin A (2) from the same animal. The compounds are of particular interest due to their biogenetically unexpected structures as well as their biological activities. The structure and absolute stereochemistry of 1 as a α,ω-bifunctionalized sphingoid tetrahydroisoquinoline ß-glycoside was elucidated using NMR, CD and MS spectral analysis and chemical degradation. Oceanalin B exhibited in vitro antifungal activity against Candidaglabrata with a MIC of 25 µg/mL.

Synthesis and evaluation of tetrahydroisoquinoline derivatives against Trypanosoma brucei rhodesiense.

Human African Trypanosomiasis (HAT) is a neglected tropical disease caused by the parasitic protozoan Trypanosoma brucei (T. b.), and affects communities in sub-Saharan Africa. Previously, analogues of a tetrahydroisoquinoline scaffold were reported as having in vitro activity (IC50 = 0.25-70.5 µM) against T. b. rhodesiense. In this study the synthesis and antitrypanosomal activity of 80 compounds based around a core tetrahydroisoquinoline scaffold are reported. A detailed structure activity relationship was revealed, and five derivatives (two of which have been previously reported) with inhibition of T. b. rhodesiense growth in the sub-micromolar range were identified. Four of these (3c, 12b, 17b and 26a) were also found to have good selectivity over mammalian cells (SI > 50). Calculated logD values and preliminary ADME studies predict that these compounds are likely to have good absorption and metabolic stability, with the ability to passively permeate the blood brain barrier. This makes them excellent leads for a blood-brain barrier permeable antitrypanosomal scaffold.

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.