Development of Cyclic N,O-Aminal-Embedded Bis-tetrahydroisoquinoline Analogues as Potential DNA Alkylation Agents.

This work described a novel "functional hybrid" design for bis-tetrahydroisoquinoline (bis-THIQ) analogues as potential DNA alkylation agents by replacing the labile C21-carbinolamine on the bis-THIQ skeleton of ET-743 with a chemically stable cyclic N,O-aminal functionality. In vitro anti-proliferation evaluation has proven that it is a successful approach to deliver new bis-THIQ analogues with common cytotoxicities, among which several exhibited sub-micromolar-range IC50 against the proliferation of human cancer cell lines A549, HepG2, and MDA-MB-231, respectively.

In-Silico Identification of Novel Pharmacological Synergisms: The Trabectedin Case.

The in-silico strategy of identifying novel uses for already existing drugs, known as drug repositioning, has enhanced drug discovery. Previous studies have shown a positive correlation between expression changes induced by the anticancer agent trabectedin and those caused by irinotecan, a topoisomerase I inhibitor. Leveraging the availability of transcriptional datasets, we developed a general in-silico drug-repositioning approach that we applied to investigate novel trabectedin synergisms. We set a workflow allowing the identification of genes selectively modulated by a drug and possible novel drug interactions. To show its effectiveness, we selected trabectedin as a case-study drug. We retrieved eight transcriptional cancer datasets including controls and samples treated with trabectedin or its analog lurbinectedin. We compared gene signature associated with each dataset to the 476,251 signatures from the Connectivity Map database. The most significant connections referred to mitomycin-c, topoisomerase II inhibitors, a PKC inhibitor, a Chk1 inhibitor, an antifungal agent, and an antagonist of the glutamate receptor. Genes coherently modulated by the drugs were involved in cell cycle, PPARalpha, and Rho GTPases pathways. Our in-silico approach for drug synergism identification showed that trabectedin modulates specific pathways that are shared with other drugs, suggesting possible synergisms.

A Comprehensive Review on the Role of Lurbinectedin in Soft Tissue Sarcomas.

OPINION STATEMENT: Soft tissue sarcoma (STS), a substantial group of aggressive and rare tumors with tissue heterogeneity, is infrequently represented in clinical trials with an urgent necessity for newer treatment options. Lurbinectedin, an analog of trabectedin, is currently approved, in various countries, as a single agent, for the treatment of patients with relapsed small cell lung cancer (SCLC). However, preclinical and phase I and phase II trials have demonstrated the efficacy of lurbinectedin in different tumor types, including STS. The better understanding of the pathophysiology and evolution of STS as well as the mechanism of action of lurbinectedin in addition to the available data regarding the activity of this drug in this subset of patients will pave the way to newer therapeutic options and strategies.

Targeting Alzheimer's Disease: Evaluating the Efficacy of C-1 Functionalized N-Aryl-Tetrahydroisoquinolines as Cholinergic Enzyme Inhibitors and Promising Therapeutic Candidates.

We have synthesized 22 C-1 functionalized-N-aryl-1,2,3,4-tetrahydroisoquinoline derivatives showing biological activities towards cholinergic enzymes. Synthesis was performed using visible-light-promoted photo-redox chemistry, starting from a common intermediate, and the application of this synthetic methodology drastically simplified synthetic routes and purification of desired compounds. All synthesized derivates were divided into four groups based on the substituents in the C-1 position, and their inhibition potencies towards two cholinergic enzymes, acetyl- and butyrylcholinesterase were evaluated. Most potent derivatives were selected, and kinetic analysis was further carried out to obtain insights into the mechanisms of inhibition of these two enzymes. Further validation of the mode of inhibition of cholinergic enzymes by the two most potent THIQ compounds, 3c and 3i, was performed using fluorescence-quenching titration studies. Molecular docking studies further confirmed the proposed mechanism of enzymes' inhibition. In silico predictions of physicochemical properties, pharmacokinetics, drug-likeness, and medicinal chemistry friendliness of the selected most potent derivatives were performed using Swiss ADME tool. This was followed by UPLC-assisted log P determination and in vitro BBB permeability studies performed in order to assess the potential of the synthesized compounds to pass the BBB.

Green approach to the synthesis of α-aminophosphonate-tetrahydroisoquinoline hybrids and their anti-cholinesterase activity.

A series of 19 novel α-aminophosphonate-tetrahydroisoquinoline hybrids were synthesized through a cross dehydrogenative coupling reaction between N-aryl-tetrahydroisoquinolines and dialkylphosphites, using tert-butyl hydroperoxide as oxidazing agent. This simple procedure provided products with high atom economy and moderate to high yields. In vitro cholinesterase inhibitory activity of these compounds was evaluated. All the synthesized compounds showed good to excellent selective inhibition against butyrylcholinesterase. Compound 3bc was found to be the most active derivative with an IC50 of 9 nM. Molecular modelling studies suggested that the inhibitor is located in the peripheral anionic site (PAS) of the enzyme and interacts with some residue of the catalytic anionic site. Kinetic studies revealed that 3bc acts as a non-competitive inhibitor. Predicted ADME showed good pharmacokinetics and drug-likeness properties for most hybrids. Each newly synthesized compound was characterized by IR, 1H NMR, 13C NMR, 31P NMR spectral studies and also HRMS. The results of this study suggest that α-aminophosphonate-tetrahydroisoquinoline hybrids can be promising lead compounds in the discovery of new and improved drugs for the treatment of Alzheimer's disease and related neurodegenerative disorders.

Synthesis of biologically important tetrahydroisoquinoline (THIQ) motifs using quantum dot photocatalyst and evaluation of their anti-bacterial activity.

Our study introduces an efficient photocatalytic approach for synthesizing biologically significant C1-substituted tetrahydroisoquinoline (THIQ) motifs, employing WS2 quantum dots (QDs) as catalysts. This method enables the formation of C-C and C-P bonds at the C1 position of the THIQ motif. The resulting compounds exhibit substantial antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA) bacteria, with low minimum inhibitory concentration (MIC) values. Notably, the WS2 QD catalyst demonstrates recyclability and suitability for gram-scale reactions, underscoring the sustainability and scalability of our approach. Overall, our research presents a versatile and cost-effective strategy for synthesizing C1-substituted THIQ derivatives, highlighting their potential as novel therapeutic agents in biology and medicinal chemistry.

N-Sulfonyl-1,2,3,4-tetrahydroisoquinoline Derivatives: Synthesis, Antimicrobial Evaluations, and Theoretical Insights.

Microbial contamination remains a significant economic challenge in the food industry, emphasizing the need for innovative antimicrobial solutions. In this study, we synthesized N-sulfonyl-1,2,3,4-tetrahydroisoquinolines (NSTHIQ) derivatives using an environmentally friendly Preyssler heteropolyacid catalyst, obtaining moderate to high yields (35-91 %) under mild conditions. Two derivatives (5 and 6) exhibited significant antifungal properties against various fungal species, including Aspergillus spp, Penicillium spp, and Botrytis cinerea. ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) analysis revealed the absence of hepatic toxicity in all compounds, making derivatives 2, 3, 4, and 5 potential candidates for further development. However, derivatives 6 and 7 exhibited immunotoxicity. In support of our experimental findings, reactivity indices were computed using Density Functional Theory principles, deriving valuable insights into the chemical properties of these derivatives. This study underscores the potential of NSTHIQ compounds as potent antifungal agents, coupled with the importance of employing environmentally friendly catalysts in drug discovery.

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.

3-[[(3S)-1,2,3,4-Tetrahydroisoquinoline-3-Carbonyl]Amino]Propanoic Acid (THICAPA) Is Protective Against Aß42-Induced Toxicity In Vitro and in an Alzheimer's Disease Drosophila.

Alzheimer's disease (AD) is the most prevalent type of dementia globally. The accumulation of amyloid-beta (Aß) extracellular senile plaques in the brain is one of the hallmark mechanisms found in AD. Aß42 is the most damaging and aggressively aggregating Aß isomer produced in the brain. Although Aß42 has been extensively researched as a crucial peptide connected to the development of the characteristic amyloid fibrils in AD, the specifics of its pathophysiology are still unknown. Therefore, the main objective was to identify novel compounds that could potentially mitigate the negative effects of Aß42. 3-[[(3S)-1,2,3,4-Tetrahydroisoquinoline-3-carbonyl]amino]propanoic acid (THICAPA) was identified as a ligand for Aß42 and for reducing fibrillary Aß42 aggregation. THICAPA also improved cell viability when administered to PC12 neuronal cells that were exposed to Aß42. Additionally, this compound diminished Aß42 toxicity in the current AD Drosophila model by rescuing the rough eye phenotype, prolonging the life span, and enhancing motor functions. Through next-generation RNA-sequencing, immune response pathways were downregulated in response to THICAPA treatment. Thus, this study suggests THICAPA as a possible disease-modifying treatment for AD.

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.

Structural optimization of tetrahydroisoquinoline-hydroxamate hybrids as potent dual ERα degraders and HDAC inhibitors.

Both estrogen receptor α (ERα) and histone deacetylases (HDACs) are valid therapeutic targets for anticancer drug development. Combination therapies using diverse ERα antagonists or degraders and HDAC inhibitors have been proven effective in endocrine-resistant ER + breast cancers based on the crosstalk between ERα and HDAC pathway. In this study, we reported the optimization of a series of methoxyphenyl- or pyridinyl- substituted tetrahydroisoquinoline-hydroxamates, which were optimized from 31, a dual ERα degrader/HDAC inhibitor previously reported by our group. Most of the synthesized compounds displayed potent ERα degradation efficacy and antiproliferative activity. Among them, A04 demonstrated the best anti-proliferation activity (MCF-7 IC50 = 1.96 µM) and HDAC6 inhibitory activity (HDAC6 IC50 = 25.96 nM), which is slightly more potent than the lead compound 31 (MCF-7 IC50 = 4.38 µM, HDAC6 IC50 = 63.03 nM). In addition, compound A04 exerted ERα-independent HDAC6-inhibiting effect without agonistic activity in endometrial cells. These results demonstrated that A04 is a novel and promising dual ERα degrader/HDAC inhibitor worthy of further development.

Matrix-Metalloproteinase Inhibitory Study of Novel Tetrahydroisoquinoline-4-carboxylates: Design, Synthesis, and Molecular Docking Studies.

The design, molecular docking, synthesis and structure-activity relationship (SAR) of a series of novel methyl 1-oxo-2-(propan-2-yl)-3-(pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylates, were investigated for antiproliferative and cytotoxic studies by screening against cancer cell lines of different origin by MTT, LDH and Trypan Blue Assay. Irrespective of cell lines, among the synthesized nonpeptido-mimetic analogs 5a-e, 5c has executed potent bio-potency with IC50 value of 7.00 to 7.21 µM, which further expressed in-vivo anti-tumor activity against murine T-cell lymphoma cell lines (Daltons Lymphoma-DLA) by regressing tumor growth. The formation of neovessels from the vasculogenesis was diminished reflecting the antitumor activity. The neovessel formation is directly relied on expression of matrix meteloproteases (MMP's) level which was drastically reduced by 5c treatment as evaluated by immonoblot assays. This is further supported by in-silico ADMET studies performed by ACD I-Lab 2.0 were in agreement with Lipinski rule of five. Reporting results were assessed as a positive parameter for further validation of the compound for therapeutic potential of cancer by 5c for preclinical studies in near future.

Synthesis of Novel 1-Oxo-2,3,4-trisubstituted Tetrahydroisoquinoline Derivatives, Bearing Other Heterocyclic Moieties and Comparative Preliminary Study of Anti-Coronavirus Activity of Selected Compounds.

A series of novel 1-oxo-2,3,4-trisubstituted tetrahydroisoquinoline (THIQ) derivatives bearing other heterocyclic moieties in their structure were synthesized based on the reaction between homophthalic anhydride and imines. Initial studies were carried out to establish the anti-coronavirus activity of some of the newly obtained THIQ-derivatives against two strains of human coronavirus-229E and OC-43. Their antiviral activity was compared with that of their close analogues, piperidinones and thiomorpholinones, previously synthesized in our group, with aim to expand the range of the tested representative sample and to obtain valuable preliminary information about biological properties of a wider variety of compounds.

Novel Tetrahydroisoquinoline-Based Heterocyclic Compounds Efficiently Inhibit SARS-CoV-2 Infection In Vitro.

The ongoing COVID-19 pandemic has caused over six million deaths and huge economic burdens worldwide. Antivirals against its causative agent, SARS-CoV-2, are in urgent demand. Previously, we reported that heterocylic compounds, i.e., chloroquine (CQ) and hydroxychloroquine (HCQ), are potent in inhibiting SARS-CoV-2 replication in vitro. In this study, we discussed the syntheses of two novel heterocylic compounds: tert-butyl rel-4-(((3R,4S)-3-(1H-indol-3-yl)-1-oxo-2-propyl-1,2,3,4-tetrahydroisoquinolin-4-yl)methyl)piperazine-1-carboxylate (trans-1) and rel-(3R,4S)-3-(1H-indol-3-yl)-4-(piperazin-1-ylmethyl)-2-propyl-3,4-dihydroisoquinolin-1(2H)-one (trans-2), which effectively suppressed authentic SARS-CoV-2 replication in Vero E6 cells. Compound trans-1 showed higher anti-SARS-CoV-2 activity than trans-2, with a half maximal effective concentration (EC50) of 3.15 µM and a selective index (SI) exceeding 63.49, which demonstrated comparable potency to CQ or HCQ. Additional anti-SARS-CoV-2 tests on Calu-3 human lung cells showed that trans-1 efficiently inhibited viral replication (EC50 = 2.78 µM; SI: > 71.94) and performed better than CQ (EC50 = 44.90 µM; SI = 2.94). The time of an addition assay showed that the action mechanism of trans-1 differed from that of CQ, as it mainly inhibited the post-entry viral replication in both Vero E6 and Calu-3 cells. In addition, the differences between the antiviral mechanisms of these novel compounds and CQ were discussed.

Design and evaluation of dibenzoazepine-tetrahydroisoquinoline hybrids as potential P-glycoprotein inhibitors against multidrug resistant K562/A02 cells.

Multidrug resistance (MDR) caused by P-glycoprotein (P-gp) is a main barrier to the success of cancer chemotherapies. In this study, fourteen novel dibenzoazepine-tetrahydroisoquinoline hybrids were prepared as potential P-gp inhibitors to surmount MDR caused by P-gp. Amongst them, 8a displayed the most potent inhibition effect on P-gp, thus effectively reversing P-gp-mediated drug resistance with a reversal fold (RF) value of 93.17 in K562/A02 cells. Excitingly, the EC50 value of 8a on MDR reversing effect was 48.74 nM, which was nearly two thousand-fold lower than its IC50 value (95.94 µM) for intrinsic cytotoxicity on K562/A02 cells. Further investigation showed that 8a exerted the MDR reversal effect through impairing P-gp function rather than affecting its expression. Molecular docking and CETSA results illustrated that 8a possessed a relatively high affinity for P-gp, thus effectively improving the stability of P-gp. Furthermore, 8a exhibited a much poorer inhibitory effect on CYP3A4 activity than CYP3A4 inhibitor ketoconazole, thus might not cause unfavorable drug-drug interactions. These data together suggested that 8a may be a promising lead to design P-gp inhibitors, and warranted further investigation on overcoming P-gp-mediated MDR.

Design, synthesis, and biological evaluation of tetrahydroisoquinoline stilbene derivatives as potential antitumor candidates.

Herein, a novel class of tetrahydroisoquinoline stilbene derivatives were synthesized, and their potential in vitro anticancer activities were evaluated. Most of the compounds displayed inhibitory activity against one or more representative human cancer cell lines (lung cancer A549 cells, breast cancer MCF-7 cells, and human colorectal carcinoma HT-29 cells), especially compound 16e, which exhibited outstanding cytotoxicity to A549 cells. The tubulin polymerization assay demonstrated that compound 16e displayed better inhibition than colchicine when tested at the same concentration. It was found that 16e arrested A549 cells in G2/M phase by downregulating the expression of cell division cycle 2 (Cdc2) and upregulating the expression of proliferating cell nuclear antigen (PCNA) and cyclin B1. Flow cytometry and Western blot analysis indicated that 16e caused apoptosis via the mitochondrial-dependent apoptotic pathway by reducing mitochondrial membrane potential, inducing ROS accumulation, promoting the release of cytochrome C from the mitochondria into the cytoplasm, and further increasing the protein level of cleaved caspase-3. This work may inspire new ideas for the further improvement of tubulin-related anticancer drugs and treatments.

Identification of N- and C-3-Modified Laudanosoline Derivatives as Novel Influenza PAN Endonuclease Inhibitors.

Influenza PAN inhibitors are of particular importance in current efforts to develop a new generation of antiviral drugs due to the growing emergence of highly pathogenic influenza viruses and the resistance to existing antiviral inhibitors. Herein, we design and synthesize a set of 1,3-cis-N-substituted-1,2,3,4-tetrahydroisoquinoline derivatives to enhance their potency by further exploiting the pockets 3 and 4 in the PAN endonuclease based on the hit d,l-laudanosoline. Particularly, the lead compound 35 exhibited potent and broad anti-influenza virus effects with EC50 values ranging from 0.43 to 1.12 µM in vitro and good inhibitory activity in a mouse model. Mechanistic studies demonstrated that 35 could bind tightly to the PAN endonuclease of RNA-dependent RNA polymerase, thus blocking the viral replication to exert antiviral activity. Overall, our study might establish the importance of 1,2,3,4-tetrahydroisoquinoline-6,7-diol-based derivatives for the development of novel PAN inhibitors of influenza viruses.

Target Identification of 22-(4-Pyridinecarbonyl) Jorunnamycin A, a Tetrahydroisoquinoline Derivative from the Sponge Xestospongia sp., in Mediating Non-Small-Cell Lung Cancer Cell Apoptosis.

A dysregulation of the cell-death mechanism contributes to poor prognosis in lung cancer. New potent chemotherapeutic agents targeting apoptosis-deregulating molecules have been discovered. In this study, 22-(4-pyridinecarbonyl) jorunnamycin A (22-(4'py)-JA), a synthetic derivative of bistetrahydroisoquinolinequinone from the Thai blue sponge, was semisynthesized by the Steglich esterification method, and its pharmacological mechanism in non-small-cell lung cancer (NSCLC) was elucidated by a network pharmacology approach. All predicted targets of 22-(4'py)-JA and genes related to NSCLC were retrieved from drug-target and gene databases. A total of 78 core targets were identified, and their associations were analyzed by STRING and Cytoscape. Gene ontology and KEGG pathway enrichment analyses revealed that molecules in mitogen-activated protein kinase (MAPK) signaling were potential targets of 22-(4'py)-JA in the induction of NSCLC apoptosis. In silico molecular docking analysis displayed a possible interaction of ERK1/2 and MEK1 with 22-(4'py)-JA. In vitro anticancer activity showed that 22-(4'py)-JA has strong cytotoxic and apoptosis-inducing effects in H460, H292 and A549 NSCLC cells. Furthermore, immunoblotting confirmed that 22-(4'py)-JA induced apoptotic cell death in an ERK/MEK/Bcl-2-dependent manner. The present study demonstrated that 22-(4'py)-JA exhibited a potent anticancer effect that could be further developed for clinical application and showed that network pharmacology approaches are a powerful tool to illustrate the molecular pathways of new drugs or compounds.

Spirofused Tetrahydroisoquinoline-Oxindole Hybrids (Spiroquindolones) as Potential Multitarget Antimalarial Agents: Preliminary Hit Optimization and Efficacy Evaluation in Mice.

Previous studies suggest that 3',5'-dihydro-2'H-spiro[indoline-3,1'-isoquinolin]-2-ones (DSIIQs [spiroquindolones]) are multitarget antiplasmodial agents that combine the actions of spiroindolone and naphthylisoquinoline antimalarial agents. In this study, 12 analogues of compound (±)-5 (moxiquindole), the prototypical spiroquindolone, were synthesized and tested for antiplasmodial activity. Compound (±)-11 (a mixture of compounds 11a and 11b), the most potent analogue, displayed low-nanomolar activity against P. falciparum chloroquine-sensitive 3D7 strain (50% inhibitory concentration [IC50] for 3D7 = 21 ± 02 nM) and was active against all major erythrocytic stages of the parasite life cycle (ring, trophozoite, and schizont); it also inhibited hemoglobin metabolism and caused extensive vacuolation in parasites. In drug-resistant parasites, compound (±)-11 exhibited potent activity (IC50 for Dd2 = 58.34 ± 2.04 nM) against the P. falciparum multidrug-resistant Dd2 strain, and both compounds (±)-5 and (±)-11 displayed significant cross-resistance against the P. falciparum ATP4 mutant parasite Dd2 SJ733 but not against the Dd2 KAE609 strain. In mice, both compounds (±)-5 and (±)-11 displayed dose-dependent reduction of parasitemia with suppressive 50% effective dose (ED50) values of 0.44 and 0.11 mg/kg of body weight, respectively. The compounds were also found to be curative in vivo and are thus worthy of further investigation.

The Tetrahydroisoquinoline Scaffold in ABC Transporter Inhibitors that Act as Multidrug Resistance (MDR) Reversers.

BACKGROUND: The failure of anticancer chemotherapy is often due to the development of resistance to a variety of anticancer drugs. This phenomenon is called multidrug resistance (MDR) and is related to the overexpression of ABC transporters, such as P-glycoprotein, multidrug resistance- associated protein 1 and breast cancer resistance protein. Over the past few decades, several ABC protein modulators have been discovered and studied as a possible approach to evade MDR and increase the success of anticancer chemotherapy. Nevertheless, the co-administration of pump inhibitors with cytotoxic drugs, which are substrates of the transporters, does not appear to be associated with an improvement in the therapeutic efficacy of antitumor agents. However, more recently discovered MDR reversing agents, such as the two tetrahydroisoquinoline derivatives tariquidar and elacridar, are characterized by high affinity towards the ABC proteins and by reduced negative properties. Consequently, many analogs of these two derivatives have been synthesized, with the aim of optimizing their MDR reversal properties. OBJECTIVE: This review aims to describe the MDR modulators carrying the tetraidroisoquinoline scaffold reported in the literature in the period 2009-2021, highlighting the structural characteristics that confer potency and/or selectivity towards the three ABC transport proteins. RESULTS AND CONCLUSION: Many compounds have been synthesized in the last twelve years showing interesting properties, both in terms of potency and selectivity. Although clear structure-activity relationships can be drawn only by considering strictly related compounds, some of the compounds reviewed could be promising starting points for the design of new ABC protein inhibitors.