CD44-targeted N-benzyltetrahydroisoquinoline derivatives as anticancer agents with high tumor-to-normal cell selectivity.

Opioid addiction constitutes a significant global health challenge. Kappa opioid receptor (KOP) modulators have demonstrated efficacy in treating resistant drug abuse cases. However, till date, no selective KOP antagonists have successfully reached the market. In this study, we employed structure-based design to modify JDTic, the most potent KOP antagonist, into a series of novel analogs based on a tetrahydroisoquinoline (THIQ)-valine hybrid scaffold. More than 20 compounds were synthesized and assessed for binding affinities to the three opioid receptor subtypes. Ten derivatives showed a binding Ki of less than 10 µM for KOP. Subsequent functional characterization using [35S]GTP-γ-S and in vivo animal models established that most of these analogs possess mixed agonist and antagonist properties for both kappa and mu opioid receptors. For example, compound (R)-10m exhibited agonist activity for KOP and MOP receptors, with IC50 values of 670 and 94.5 nM, respectively. Subsequent testing indicated that (R)-10m possesses an analgesic profile with a comparable latency to the positive control, Nalbuphine, in the tail-flick animal model, while compound (S)-10h was found to be a sub-micromolar KOP/MOP antagonist. These results suggest that incorporating relatively bulky and hydrophobic appendages to the privileged THIQ-valine scaffold is necessary to retain and fine-tune the affinity and selectivity for KOP.

Sequential assembly of donor-acceptor components at the molecular level within a MOF is an effective strategy to achieve efficient electron-hole separation for enhancing the activity of photocatalysts. Meanwhile, the highly efficient and selective functionalization of tetrahydroisoquinoline (THIQ) under mild conditions remains an urgent demand in both the scientific and industrial communities. This work reports a donor-acceptor MOF photocatalyst (PDI-MOF) constructed by the coordinated assembly of donor and acceptor components, in which a naphthalene unit serves as an electron donor and a perylenediimide unit as an electron acceptor. The PDI-MOF can undergo rapid photoinduced electron transfer and exhibits long-lived charge-separated states with prominent photochromism. The photogenerated charges can rapidly activate the substrates THIQ and O2, thereby achieving a highly selective coupling reaction of the C-C and C-P bonds of THIQ. In addition to the gram-scale reaction, PDI-MOF can also be applied to conduct photocatalytic reactions under natural sunlight and ambient air, highlighting its prospects for industrial application.

Recent advances in the Total synthesis and structural modification of Ecteinascidin-743.

The enantioselective functionalization of inert C(sp3)-H bonds is one of the most significant challenges in modern synthetic chemistry, especially when it is applied to structurally complex compounds. To achieve success, we require a comprehensive understanding of the mechanisms involved in controlling enantioselectivity, but such knowledge is currently limited. Herein, we systematically investigated the catalysis of chiral iridium complexes for the C(sp3)-H borylation of tetrahydroisoquinoline (THIQ) using DFT calculations with a careful conformational search of transition states. Our results reveal that the active species are iridium(III) tris(boryl) diastereomers bearing chiralities at both the Ir center (Λ or Δ) and (S,S)-pyridyl-boryl ligand (CBL). This reaction proceeds via enantioselective C(sp3)-H activation at the α-methylene position of THIQ, changes in hydride and boryl coordination sites, and B-C reductive elimination as the rate-determining step. R-product is calculated to be produced more than S-one, as experimentally observed. The difference in activation energy between Λ- and Δ-Ir catalysts is 3.60 kcal mol-1 (99% ee), which agrees with the experimentally observed ee value (94%). Crucially, neglecting Ir-centered Λ/Δ chirality leads to unrealistic 100% ee predictions regardless of CBL substituents, whereas incorporating both metal and ligand chiralities successfully reproduces the substituent-dependent ee trends observed experimentally. The greater selectivity of the R-product over the S-one is attributed to the larger reaction pocket of the transition state of the B-C reductive elimination in the R-product formation than that in the S-one. This work provides fundamental insights into the cooperative stereochemical roles of metal and ligand chiralities in asymmetric C-H borylation.

Abstract In this research we represented a simple and elegant method for 3,3‐disubstituted THIQs via base‐mediated [4 + 2] annulation of α‐amino acid ester derivatives and 1,2‐bis(bromomethyl)benzene under mild conditions. This protocol features good substrate tolerance, mild conditions and moderate to excellent yields. The synthetic potential of this protocol was highlighted by scale‐up experiments and further structural elaboration.

Sigma receptors (σRs), comprising σ1 and σ2 subtypes, are versatile pharmacological targets with significant roles in cancer, neurodegeneration, and psychiatric disorders. The tetrahydroisoquinoline (THIQ) scaffold, a core structure in many biologically active compounds, has garnered attention as a versatile platform for designing σRs ligands. THIQ-based compounds exhibit potent σRs binding affinity, leading to therapeutic effects ranging from neuroprotection to antitumor activity. This mini-review explores the structural features of THIQ ligands, their interaction with σRs, and their therapeutic implications. Challenges and future prospects for THIQ derivatives in σRs research are also discussed.

BackgroundStress is a major trigger for migraine attacks. Stress activates the hypothalamic-pituitary-adrenal (HPA) axis, releasing glucocorticoids (GCs) to maintain homeostasis, and migraine attacks may occur as an adverse effect of this response. We previously demonstrated in a mouse model that inhibiting corticosterone (CORT) synthesis by administering metyrapone before stress prevented stress-induced migraine-like behaviors. Given the unpredictable nature of stressors and their onset or termination, it is critical to better understand the adaptive and maladaptive effects of the HPA stress response. Here, we aimed to evaluate the effects of HPA axis modulation following the end of stress exposure.MethodsRepeated stress induces migraine-like behaviors and priming to sodium nitroprusside (SNP) in mice. Metyrapone (to inhibit CORT synthesis), CORT (to evaluate its effects after exogenous administration), and adrenocorticotropic hormone (ACTH) (to test the effects of a hormone upstream to CORT) were administered post-stress. Additionally, α-melanocyte-stimulating hormone (α-MSH, an ACTH cleavage product) and tetrahydroisoquinoline (THIQ), a melanocortin 4 receptor (MC4R) agonist, were administered to examine melanocortin receptor involvement. Facial hypersensitivity was assessed via von Frey testing and grimace scoring was used to evaluate non-evoked pain. Serum CORT levels were measured in both control and stressed mice following ACTH administration.ResultsWe examined post-stress HPA axis modulation on stress-induced facial hypersensitivity. Metyrapone reduced acute-phase hypersensitivity and reduced priming to SNP, suggesting sustained synthesis of CORT after stress plays a role in development of migraine-like behavior. Surprisingly, both CORT and ACTH treatments at 1- and 24-h post-stress alleviated stress-induced behaviors and priming. To determine if ACTH effects were mediated by an elevation in circulating CORT, metyrapone was administered before the ACTH injection. Metyrapone increased the ACTH reversal of stress effects on facial hypersensitivity. Furthermore, post-stress ACTH injections significantly increased serum CORT levels within 30 min. In addition to ACTH effects on CORT levels, ACTH effects could be mediated by the melanocortin system. Post-stress administration of α-MSH or the MC4R agonist THIQ, reduced migraine-like behaviors.ConclusionsThere is a complex relationship between stress, the HPA axis, and melanocortin signaling, in the effects of repeated stress exposure on migraine-like behaviors. In the early post-stress response phase, there are contributions from both CORT and MC4R signaling in the maintenance of behavioral effects. These findings suggest that targeting the HPA axis and MC4R after stress may be a potential therapeutic approach for stress-induced migraine attacks.

Self-immolative linkers that use p-amino/hydroxy-benzyloxycarbonyl (PABC/PHBC) spacers are essential to the mechanism of many prodrugs. However, a highly reactive (aza)quinone methide is generated as a potential toxic byproduct. To remove the methide as it forms, we synthesized a series of novel tripartite prodrugs, comprising different triggers (nitro, amide, azide, boronate) and a PABC/PHBC-type self-immolative spacer with an integrated nucleophile (amine). Upon reductive, hydrolytic, or oxidative-trigger activation, the release of the cargo is facilitated via a 1,6-elimination that generates a reactive (aza)quinone methide. With the built-in nucleophile, the (aza)quinone methide is rapidly self-quenched to generate tetrahydroisoquinolines (THIQs). One of the selected THIQs does not exhibit an anti-proliferative effect on the A431 mammalian tumor cell line. The new prodrug strategy has broad scope, enabling the use of a trigger that matches the targeted stimulus, while allowing for a diverse range of drug/cargo attachment. This proof-of-concept study adds a new linker strategy that quenches the electrophilic (aza)quinone methide generated in many self-immolative linker systems and could find applications in prodrug and antibody-drug conjugate strategies, or as a linker for probes in chemical biology.

Tetrahydroisoquinoline (THIQ) oximes have been investigated as antidotes for poisoning by toxic organophosphorus compounds. Recent studies have shown that some THIQ oximes induce cytotoxic effects and trigger apoptosis in various cell types. Since this pathway activation is desirable for anticancer drugs, we further explored the effects of three selected THIQ oximes on well-known cancer cell models: breast (MDA-MB-231 and MCF-7), prostate (PC-3) cancer and malignant glioblastoma (U251). The tested THIQ oximes were cytotoxic to breast cancer cells and, to a lesser extent, to glioblastoma cells, but not to PC-3 cells at concentrations up to 200 µM within a 24-h exposure period. The MCF-7 cells exhibited the highest sensitivity, with all three oximes affecting it in a time-dependent manner (IC50 from 7–74 µM). While the membrane integrity of affected cells was maintained after treatment with the tested THIQ oximes, they disrupted mitochondrial membrane potential and activated caspase 9 indicating triggering of the mitochondria-mediated apoptosis. Overall, these findings suggest that the THIQ oxime scaffold could be a foundation for developing targeted therapies, especially for breast cancer, and other derivatives may be worthier of exploration.

Although MK801-induced NMDA receptor (NMDAR) hypofunction mimics schizophrenia symptoms, the exact factors causing NMDAR inhibition are unknown. Unexpectedly, external stress elicits formaldehyde (FA) generation; FA can induce depression and cognitive impairments by blocking NMDARs. This study explores using FA injection to establish a schizophrenia-like model in mice. Here, we reported that external stress-derived FA induces schizophrenia-like behaviors. Four experimental methods were used to induce schizophrenia-like symptoms in wild-type mice: double electrode stimulation of the ventral tegmental area (VTA), microinjection of FA or tetrahydroisoquinoline (TIQ) into the VTA, and intraperitoneal injection of MK801. Then the metabolic levels of FA and dopamine (DA) in the prefrontal cortex (PFC) and VTA were quantified using ELISA kits. We found that external stress-electrical stimulation via VTA caused schizophrenia-like behaviors, including despairing behavior as measured by the tail suspension test, anhedonia as evaluated by the sucrose preference test, stereotypical behavior as assessed by the marble burying test (MBT), anxiety-like behavior as measured by the open-field test and memory deficit as detected by the Y-maze. These behaviors correlated with increased DA and TIQ levels in the VTA and decreased DA levels in the PFC. High-resolution mass spectrometry (HRMS) and high-performance liquid chromatography (HPLC) confirmed TIQ formation from FA and DA. Furthermore, injecting TIQ into the VTA induced schizophrenia-like symptoms in mice, marked by higher FA and lower DA levels in the PFC than control mice. Strikingly, injecting FA into the VTA as well as administering MK-801 induced schizophrenia-like behaviors associated with reduced DA levels and low activity of tyrosine hydroxylase (TH) and monoamine oxidase (MAO) in the PFC. Hence, microinfusion of FA into the VTA can be used to prepare schizophrenia-like changes mouse model, suggesting that stress-derived FA may act as an endogenous trigger of schizophrenia-like changes.

Abstract We present a decarboxylative cross‐dehydrogenative coupling (CDC) reaction between tetrahydroisoquinoline (THIQ) derivatives and alkynoic acids using a carbon nanotube‐supported copper/nickel oxide (CNT‐CuO/Ni) catalyst. This catalyst leverages the catalytic properties of copper and magnetic recoverability of nickel to facilitate efficient carbon─carbon bond formation under mild conditions while allowing for easy separation and reuse. Under optimized conditions, the reaction produced various 1‐alkynyl‐2‐aryl‐1,2,3,4‐tetrahydroisoquinoline derivatives in good yields. The CNT‐CuO/Ni catalyst exhibited significant reusability, retaining high catalytic performance through 12 reaction cycles. Competition experiments revealed that the electronic properties of substituents on the phenyl propiolic acid and THIQ aryl groups had a minimal effect on the reaction outcome. This study underscores the potential of CNT‐CuO/Ni as a recyclable catalyst for sustainable organic synthesis in decarboxylative CDC reactions.

Quercetin, a well-known flavonoid with significant medicinal potential, was derivatized at the C8 position with a tetrahydroisoquinoline (THIQ) moiety, and physicochemical and pharmacological properties, inhibition potential, antioxidant activity, and cytotoxicity of new compounds were evaluated. Physicochemical and pharmacological properties, including lipophilicity, membrane permeability, and P-glycoprotein substrate affinity, were assessed theoretically using the SwissADME software. The metal-chelating ability of the new compounds was evaluated on metal ions Fe2+, Zn2+, and Cu2+, whose homeostasis disruption is linked to the development of Alzheimer's disease. Inhibition potential was tested on the cholinergic enzymes acetylcholinesterase and butyrylcholinesterase, as well as Na+, K+-ATPase, an enzyme commonly overexpressed in tumours. Antioxidant potential was assessed using the DPPH assay. Cytotoxicity studies were conducted on healthy MRC-5 cells and three cancer cell lines: HeLa, MDA-231, and MDA-468. The results indicated that derivatization of quercetin with THIQ yielded compounds with lower toxicity, preserved chelating ability, improved antioxidant potential, increased selectivity toward the cholinergic enzyme butyrylcholinesterase, and enhanced inhibition potential toward Na+, K+-ATPase and butyrylcholinesterase compared to quercetin alone. Therefore, the synthesized derivatives represent compounds with an improved profile and could be promising candidates for further optimization in developing drugs for neurodegenerative and cancer diseases.

The asymmetric synthesis of tetrahydroisoquinolines (THIQs) has gained importance in recent years due to their significant potential in drug development studies. In this study, the conversion of 1-methyl-3,4-dihydroisoquinoline substrate to a chiral amine, 1-methyl-1,2,3,4-tetrahydroisoquinoline, under the catalysis of the stereoselective imine reductase enzyme from Stackebrandtia nassauensis (SnIR) was investigated in detail to elucidate the mechanism and explain the experimental enantioselectivity. The results were found to be in agreement with the experimental data. To elucidate the reaction mechanism, quantum mechanical calculations were performed by considering a large cluster of the active site of the enzyme. In this regard, possible reaction pathways leading to both R- and S-products with the corresponding intermediates and the transition states for the hydride transfer from the cofactor to the substrate were considered by density functional theory (DFT) calculations, and the factors contributing to the observed stereoselectivity were sought. The calculations supported a stepwise mechanism rather than the concerted protonation and the hydride transfer steps. The stereoselectivity in the hydride transfer was found to be due not only to the stability of the enzyme-subtrate complex but also to the corresponding reaction barriers. The calculations were performed at the wB97XD/6-311+G(2df,2p)//B3LYP/6-31G(d,p) level of theory using the PCM approach.

This study conducts a systematic investigation into the catalytic mechanism of norcoclaurine synthase (NCS), a key enzyme in the biosynthesis of tetrahydroisoquinolines (THIQs) with therapeutic applications. By integration of LiGaMD and DFT calculations, the reaction pathway of NCS is mapped, providing detailed insights into its catalytic activity and selectivity. Our findings underscore the critical role of E103 in substrate capture and reveal the hitherto unappreciated influence of nonpolar residues M183 and L76 on tunnel dynamics. A prominent discovery is the identification of a high-energy barrier (44.2 kcal/mol) associated with the aromatic electrophilic attack, which pinpoints the rate-limiting step. Moreover, we disclose the existence of dual transition states leading to different products with the energetically favored six-membered ring formation consistent with experimental evidence. These mechanistic revelations not only refine our understanding of NCS but also advocate for a renewed emphasis on enzyme tunnel engineering for optimizing THIQs biosynthesis. The research sets the stage for translating these findings into practical enzyme modifications. Our results highlight the potential of NCS as a biocatalyst to overcome the limitations of current synthetic methodologies, such as low yields and environmental impacts, and provide a theoretical contribution to the efficient, eco-friendly production of THIQs-based pharmaceuticals.

Herein, we report a mild and operationally simple photoredox/NHC dual catalysis strategy for the α-carboxylation of tertiary amine C(sp3)-H bonds using diethyl pyrocarbonate. This method offers a novel approach for synthesizing α-amino acid derivatives. The protocol features a broad substrate scope, accommodating both N-aryl tetrahydroisoquinolines (THIQ) and N-methyl aniline and is scalable to gram quantities. Additionally, it is suitable for the late-stage derivatization of certain pharmaceutical compounds.

Isoquinolines are ubiquitous arenes found in many biologically useful molecules. While direct substitution at the heterocyclic ring is uncommon, reductive functionalization to form tetrahydroisoquinolines (THIQs) is straightforward. Herein, we describe a facile method for producing C4-functionalized isoquinolines from a readily available parent THIQ. This high-temperature transformation utilizes pyridine-N-oxide as an oxidant generating only volatile side products and is functional-group-tolerant.

Multiple myeloma (MM) is a neoplastic condition resulting from the uncontrolled expansion of B-cell-derived plasma cells. The importance of angiogenesis in MM development has also been demonstrated. Extracellular vesicles (EVs) have vital functions in interactions between neighboring cells, such as angiogenesis. The objective of this in vitro study was to examine the transfection and angiogenesis effects of MM-EVs on endothelial cells (ECs) upon treatment with Tetrahydroisoquinoline (THIQ) as a bioactive organic compound derivative from isoquinoline. Following treatment of multiple myeloma cells (U266) with THIQ, MM-EVs were harvested and transmigrated to human umbilical vein endothelial cells (HUVEC) in a co-culture model. EVs transmigration was traced by flow cytometry. Correspondingly, the expression of angiogenic genes and/or proteins in U266 cells and HUVECs was measured by RT-PCR and ELISA methods. Likewise, the proliferation and migration of HUVECs treated with THIQ-treated MM-EVs were visualized and estimated by performing both tube formation and scratch wound healing methods. Surprisingly, the anti-angiogenic effect of THIQ-treated MM-EVs was evident by the decreased expression of CD34, VEGFR2, and IL-6 at the mRNA and/or protein levels after internalization of MM-EVs in HUVEC. Finally, tube formation and scratch wound healing experiments showed inhibition of HUVEC cell proliferation and migration by THIQ-treated MM-EVs compared to control MM-EVs. MM-EVs derived from THIQ-treated myeloma cells (U266) inhibited angiogenesis in HUVECs. This phenomenon is coordinated by the internalized THIQ-treated MM-EVs in HUVECs, and ultimately the reduction of angiogenic factors and inhibition of tube formation and scratch wound healing.

Abstract While a pharmaceutically intriguing scaffold, 5,6‐dihydropyrrolo[2,1‐a]isoquinoline (DHPIQ), has precedently been prepared from diverse tetrahydroisoquinolines (THIQs) using elaborate conditions, convenient metal‐free methods were discovered from condensation of cyanomethylene‐THIQ (1) and α‐halo‐ketones or aldehydes (1a) to afford 15 DHPIQs (2–16) in moderate yields by employing unique reactivities of the secondary amine and α‐carbon to the nitrile of 1. Preliminary biological studies with chronic myelogenous leukemia K562 and adriamycin‐resistant K562 (K562/ADM) cells exhibited some of the DHPIQs tested were active in the both cell lines. In particular, cyclohexyl‐fused DHPIQ (10) showed GI50 values of 9.79 and 13.60 μM in K562 and K562/ADM cells, respectively. Based on the flow cytometry analysis of 10, the anti‐cancer activity could be from apoptosis‐related mechanisms. Overall, this DHPIQ scaffold may be further optimized to discover clinically meaningful anti‐leukemic agents overcoming adriamycin resistance.

Integration of hydrogen evolution with the oxidation of organic substances in one electrochemical system is highly desirable. However, achieving selective oxidation of organic substances in the integrated system is still highly challenging. In this study, a phosphorylated NiMoO4 nanoneedle-like array was designed as the catalytic active electrode for the integration of highly selective electrochemical dehydrogenation of tetrahydroisoquinolines (THIQs) with hydrogen production. The leaching of anions, including MoO42- and PO43-, facilitates the reconstruction of the catalyst. As a result, nickel oxyhydroxides with the doping of PO43- and richness of defects are in situ formed. In situ Raman and density functional theory calculations have shown that the high catalytic activity is attributed to the in situ formed PO43- involved NiOOH substance. In the dehydrogenation process, the involved C-H bond but not the N-H bond is first destroyed. A two-electrode system was then fabricated with the optimized electrode that shows a benchmark current density of 10 mA cm-2 at 1.783 V, providing a yield of 70% for dihydroisoquinolines. A robust stability was also shown for this integrated electrochemical system. The understanding of the reconstruction behavior and the achievement of selective dehydrogenation will provide some hints for electrochemical synthesis.