Isoquinoline Scaffold Research Articles

An Overview on the Synthesis of Lamellarins and Related Compounds with Biological Interest.

Lamellarins are natural products with a [3,4]-fused pyrrolocoumarin skeleton possessing interesting biological properties. More than 70 members have been isolated from diverse marine organisms, such as sponges, ascidians, mollusks, and tunicates. There is a continuous interest in the synthesis of these compounds. In this review, the synthetic strategies for the synthesis of the title compounds are presented along with their biological properties. Three routes are followed for the synthesis of lamellarins. Initially, pyrrole derivatives are the starting or intermediate compounds, and then they are fused to isoquinoline or a coumarin moiety. Second, isoquinoline is the starting compound fused to an indole moiety. In the last route, coumarins are the starting compounds, which are fused to a pyrrole moiety and an isoquinoline scaffold. The synthesis of isolamellarins, azacoumestans, isoazacoumestans, and analogues is also described. The above synthesis is achieved via metal-catalyzed cross-coupling, [3 + 2] cycloaddition, substitution, and lactonization reactions. The title compounds exhibit cytotoxic, multidrug resistance (MDR), topoisomerase I-targeted antitumor, anti-HIV, antiproliferative, anti-neurodegenerative disease, and anti-inflammatory activities.

Nature-Inspired 1-Phenylpyrrolo[2,1-a]isoquinoline Scaffold for Novel Antiproliferative Agents Circumventing P-Glycoprotein-Dependent Multidrug Resistance.

Previous studies have shown that some lamellarin-resembling annelated azaheterocyclic carbaldehydes and related imino adducts, sharing the 1-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline (1-Ph-DHPIQ) scaffold, are cytotoxic in some tumor cells and may reverse multidrug resistance (MDR) mediated by P-glycoprotein (P-gp). Herein, several novel substituted 1-Ph-DHPIQ derivatives were synthesized which carry carboxylate groups (COOH, COOEt), nitrile (CN) and Mannich bases (namely, morpholinomethyl derivatives) in the C2 position, as replacements of the already reported aldehyde group. They were evaluated for antiproliferative activity in four tumor cell lines (RD, HCT116, HeLa, A549) and for the ability of selectively inhibiting P-gp-mediated MDR. Lipophilicity descriptors and molecular docking calculations helped us in rationalizing the structure-activity relationships in the P-gp inhibition potency of the investigated 1-Ph-DHPIQs. As a main outcome, a morpholinomethyl Mannich base (8c) was disclosed which proved to be cytotoxic to all the tested tumor cell lines in the low micromolar range (IC50 < 20 μM) and to inhibit in vitro the efflux pumps P-gp and MRP1 responsible for MDR, with IC50s of 0.45 and 12.1 μM, respectively.

Harnessing the Potential of Electron Donor-Acceptor Complexes and N-Centered Radicals: Expanding the Frontiers of Isoquinoline Derivative Synthesis.

Research on synthesizing nitrogen-containing heterocyclic scaffolds is important because these structures are commonly found in Nature, such as in the alkaloids' family. In our study, we propose a new method to synthesize the isoquinoline core using an electron donor-acceptor (EDA) complex strategy. Our mechanistic investigations have confirmed that our synthesis process operates through an EDA mechanism, which is not extensively discussed in the literature, particularly regarding its applications on alkynyl substrates. This EDA strategy has proven to be a simple and straightforward way to produce isoquinoline scaffolds and their derivatives without the need for metal catalysts.

Pd-Catalyzed cascade Heck cyclization/carbonylation of indoles with aryl formates: enantioselective construction of indolo[2,1-a]isoquinolines.

An efficient palladium-catalyzed cascade cyclization/carbonylation of indoles with aryl formates to access ester-functionalized indolo[2,1-a]isoquinoline scaffolds has been developed. In addition, an asymmetric variant is also achieved using a chiral phosphine ligand, affording the indolo[2,1-a]isoquinoline products in good yields and enantioselectivities.

Pyrrolo[2,1-a]isoquinoline scaffolds for developing anti-cancer agents.

Fused pyrrolo[2,1-a]isoquinolines have emerged as compelling molecules with remarkably potent cytotoxic activity and topoisomerase inhibitors. This comprehensive review delves into the intricate world of this family of compounds, analyzing the natural marine lamellarins known for their diverse and complex chemical structures, exploring structure-activity relationships (SARs), and highlighting their remarkable versatility. The review emphasizes their fundamental role as topoisomerase inhibitors and cytotoxic agents, as well as some crucial aspects of the chemistry of pyrrolo[2,1-a]isoquinolines, exploring synthetic strategies in total synthesis and molecular diversification trends, highlighting their importance in the field of medicinal chemistry and beyond.

An ICT-based highly fluorescent isoquinoline scaffold for selective Hg(II) detection in real-water samples: Development of a smart, low-cost RGB-Arduino electronic platform

Selective detection and quantification of Hg2+ ions is crucial to minimize health and environmental risks. Fluorescent organic small-molecule probes have been expeditiously utilized owing to their unique set of improved properties. However, isoquinoline core has not been extensively explored as a fluorescence platform partly due to synthetic challenges. Herein, a serendipitously discovered synthetic route to access a small yet highly functionalized novel isoquinoline-based probe, IQ is reported. The synthesis is achieved through the in-situ generation of ammonia, followed by intermolecular [5C + 1 N] aza-annulation reaction with a ketendithioacetal-based precursor, P-IQ. IQ displayed excellent recognition ability towards Hg2+ ions in H2O:ACN (99:1, v/v) via ICT-off fluorescent quenching behavior. Comparative FT-IR, 1H/13C NMR, mass spectral studies, and DFT analyses were carried out to validate the suggested mechanisms. Reversible studies confirm the secondary recognition effect of in-situ generated (IQ + Hg2+) complex on cysteine. The binding constant and LOD were estimated to be 3.7 × 104 M−1 and 0.86 µM, respectively. Further, IQ was utilized to evaluate the mercury ion content in real water samples demonstrating its effectiveness in water quality monitoring. The practical utility of IQ was further explored by developing TLC strips, Whatman filter-paper strips, and a low-cost, portable Arduino-based platform. Arduino microcontroller is interfaced with an RGB sensor to detect color changes and quantify mercury concentration w.r.t. RGB values.

Divergent and Nucleophile-Assisted Rearrangement in the Construction of Pyrrolo[2,1-b][3]benzazepine and Pyrido[2,1-a]isoquinoline Scaffolds.

Under microwave (MW) irradiation at 150 °C in toluene and in the presence of nucleophiles (DMAP, triphenylphosphine and tetrahydrothiophene) 1-substituted 1-ethynyl-2-vinyldi- and tetrahydroisoquinolines undergo [3,3]-sigmatropic rearrangement providing pyrrolo[2,1-b][3]benzazepines in good yields. The replacement of toluene with acetonitrile directs the rearrangement towards the formation of 7,11b-dihydro-6H-pyrido[2,1-a]isoquinolines.

Identification of novel 3-aryl-1-aminoisoquinolines-based KRASG12C inhibitors: Rational drug design and expedient construction by C[sbnd]H functionalization/annulation

Developing a synthetic methodology to expediently construct a specific drug scaffold with the desired biological activity remains challenging. Herein, we describe a work on rational application of a synthetic methodology in the synthesis of KRASG12C inhibitors. Novel KRASG12C inhibitors were initially designed with 1-amino-3-aryl isoquinoline scaffold using structure-based drug design strategy. A ruthenium-catalyzed direct monoCH functionalization/annulation cascade reaction of amidines and sulfoxonium ylides was then developed with high versatility of substrates and good tolerance for polar functional groups. By using this reaction, the target compounds 1-amino-3-aryl isoquinolines were facilely prepared. Further in vitro tests led to identification of two novel lead compounds with KRASG12C inhibitory activity.

Structure-based discovery of novel cruzain inhibitors with distinct trypanocidal activity profiles

Over 110 years after the first formal description of Chagas disease, the trypanocidal drugs thus far available have limited efficacy and several side effects. This encourages the search for novel treatments that inhibit T. cruzi targets. One of the most studied anti-T. cruzi targets is the cysteine protease cruzain; it is associated with metacyclogenesis, replication, and invasion of the host cells. We used computational techniques to identify novel molecular scaffolds that act as cruzain inhibitors. First, with a docking-based virtual screening, we identified compound 8, a competitive cruzain inhibitor with a Ki of 4.6 μM. Then, aided by molecular dynamics simulations, cheminformatics, and docking, we identified the analog compound 22 with a Ki of 27 μM. Surprisingly, despite sharing the same isoquinoline scaffold, compound 8 presented higher trypanocidal activity against the epimastigote forms, while compound 22, against the trypomastigotes and amastigotes. Taken together, compounds 8 and 22 represent a promising scaffold for further development of trypanocidal compounds as drug candidates for treating Chagas disease.

Luminescent furo[2,3-c]isoquinolines as fluorophores - Tuning the luminophore by donor substitution

A new library of the uncommon furo[2,3-c]isoquinoline scaffold has been synthesized by coupling the Ugi multicomponent reaction with a complex one-pot Pd-mediated double cyclization. The highly convergent and diversity-oriented approach has been exploited to introduce substituents with electron donor properties directly linked to the scaffold in the most representative positions 1 and/or 8. Moreover, the influence of an aromatic ring used as spacer between the scaffold and the electron donor substituent, as well as the substitution of the phenyl substituent in position 1 with a thiophene, on the photophysical properties have been investigated. Upon UV excitation part of the new molecules are intensively blue luminescent but for an amino donor substituent a significant switch to green emitters has been observed even upon eyesight. The electronic structure has been semiquantitatively rationalized by DFT and (TD)DFT calculations.

Palladium-Catalyzed Carbonylative Synthesis of Amide-Containing Indolo[2,1-a]isoquinolines from Alkene-Tethered Indoles and Nitroarenes

In this new procedure, amide-containing indolo[2,1-a]isoquinoline scaffolds were prepared by palladium-catalyzed carbonylative cyclization of alkene-tethered indoles with nitroarenes. By using Mo(CO)6 as the CO source and reductant and nitroarenes as the nitrogen source, this reaction produced various amide-containing indolo[2,1-a]isoquinoline derivatives in good yields in general. Furthermore, the late-stage modifications of bioactive molecules using this protocol were demonstrated as well.

Rh(III)-catalysed site-selective alkylation of β-carbolines/isoquinolines and tandem C[sbnd]H/C[sbnd]N functionalization to construct indolizine-indole frameworks

The rhodium-catalysed ortho-selective carbenes insertion strategy to activate the non-acidic sp2 CH bond of β-carboline and isoquinoline scaffolds was developed. This transformation endows facile fabrication of CC bond with high atom economy, pleasant yields and wide functional group tolerance exploiting directing properties of pyridinic nitrogen. In this protocol, diazo compounds of diethyl malonate, dimethyl dimedone and oxindole are tested as carbene source with the release of environmentally benign N2 gas as the by-product. Moreover, to perceive mechanistic insights, ESI-MS studies were conducted, and the key intermediates associated with this transformation were identified. In addition, the metal-free construction of planar polycyclic indolizine-indole frameworks has been accomplished from the synthesized products. Furthermore, the neoplastic and fluorescence properties of CN annulated compounds were also determined.

Palladium-catalyzed carbonylative cyclization of alkene-tethered indoles with phenols or arylboronic acids: Construction of carbonyl-containing indolo[2,1-a]isoquinoline derivatives

A novel palladium-catalyzed carbonylative cyclization of alkene-tethered indoles with phenols or arylboronic acids is described, which provides a facile approach to access indolo[2,1-a]isoquinoline scaffolds. This method employs benzene-1,3,5-triyl triformate (TFBen) as the CO surrogate for the incorporation of a carbonyl group into indolo[2,1-a]isoquinoline scaffolds, and a variety of carbonyl-containing indolo[2,1-a]isoquinoline derivatives are prepared in good yields.

1297-P: Berberine Derivatives as Novel Antidiabetes Agents Targeting Intestinal AMPK and Antimicrobial Peptide-Controlled Gut Microbiome

Mammalian 5′-AMP-activated protein kinase (AMPK) is a key nutrient sensor for maintaining cellular energy status and a known therapeutic target for glucose control in type 2 diabetes (T2D) . Despite current understandings of its well-established roles in regulating glucose metabolism in various tissues, AMPK functions in the intestine, the first-line organ for nutrient processing, remains largely elusive. We have uncovered a novel link between intestinal AMPK activation and brown adipose tissue (BAT) thermogenic regulation through modulating the anti-microbial peptide (AMP) -controlled gut microbiota and their metabolites. Therefore, the intestinal AMPK-AMP-microbiota-BAT axis is a potential target for the treatment of T2D. Berberine, a quaternary ammonium protoberberine alkaloid with an isoquinoline scaffold isolated from medicinal herbs, has been used to treat T2D in animal models as well as human trials, while offsetting renal, cardiovascular, hepatic, and respiratory risks. However, its poor bioavailability severely limits its application and development. As such, there is a dire need to explore structural modifications of berberine to obtain better pharmacological properties and elucidate its underlying mechanisms of action. Berberine can activate AMPK indirectly by inhibition of mitochondrial respiration in the adipocyte, myotubes and liver; however, its effects on intestinal AMPK are still unknown. We have successfully synthesized natural and non-natural novel berberine derivatives. We will determine their antidiabetes effects and elucidate the underlying mechanisms of action in targeting the intestinal AMPK-AMP pathways for T2D treatment. Moreover, our study will provide a better structure-activity relationship to guide the future design of berberine derivatives with higher potency and improved bioavailability. Disclosure E.Zhang: None.

Synthesis, crystal structure and self-assembly of novel ninhydrin-derived isoquinoline compounds

Isoquinoline skeletons are ubiquitous in natural products and pharmaceuticals with broad range of biological activity. In the present work, novel isoquinoline compounds are synthesized via the insertion of suitable nucleophile into the ninhydrin core. The reaction of ninhydrin with acetamide in refluxing AcOH afforded indanedione linked isoquinoline derivative 1. On the other hand, treatment of ninhydrin-4-methoxyphenol adduct 2 with ortho phenylenediamine in EtOH/AcOH led to the formation of isoquinoline fused benzimidazole scaffold 3. In DMSO‑d6 medium, compound 3 get oxidized to the corresponding isoquinolinone form 4. Single crystal X-ray diffraction study revealed that isoquinoline derivative 1 self-assembled to form zipper arrangement. Interestingly, fused isoquinoline scaffold 4 was found to display supramolecular helical arrangement in the crystalline state. The role of weak intermolecular interactions for development of supramolecular structure has been analysed and quatified using Hirshfeld surface analysis. The scanning electron microscopy (SEM) images of compound 1 show the formation of vesicular structure, whereas structurally analogous compounds 3 and 4 exhibit fibrilllar morphology.

Novel Biosynthetic Route to the Isoquinoline Scaffold.

Isoquinoline alkaloids are a large class of natural products with a broad range of biological activities, including antimicrobial, antitumor, antileukemic and anti-inflammatory properties. Although mostly found in plants, isoquinolines can also be found in the extracts of bacterial and fungal cultures. Regardless of the origin, most of the reported biosynthetic routes for isoquinolines use tyrosine as a main biosynthetic precursor. Here, we report the identification of a new biosynthetic pathway for production of isoquinolinequinone alkaloid mansouramycin D in Streptomyces albus Del14. Using feeding, mass spectrometry, and nuclear magnetic resonance spectroscopy, we demonstrate that tryptophan serves instead of tyrosine as a main mansouramycin biosynthetic precursor. The biosynthetic genes were identified in the chromosome of the strain by using gene inactivation and heterologous expression. Insights into the biosynthesis of mansouramycins are also presented.

Rhodium(III)-Catalyzed Cascade Reactions of Imines/Imidates with 4-Hydroxy-2-alkynoates to Synthesize Regioselective Furanone-Fused Isoquinoline Scaffolds.

A regioselective synthesis of furanone-fused isoquinoline heterocycles is developed in a single step using a Rh(III) catalyst. In this reaction, a cascade C-H activation, regioselective annulation, and lactonization occur in one pot. A wide range of alkynoates was examined, which showed good regioselectivity. The regioselectivity was guided by steric bulk at the C4 position of the 4-hydroxy-2-alkynoates. The synthetic utility was exemplified, and the model reaction was scaled up to a 1 g scale.

Design, structure-activity relationship study and biological evaluation of the thieno[3,2-c]isoquinoline scaffold as a potential anti-cancer agent

Several derivatives of a series that share a thienoisoquinoline scaffold have demonstrated potent activity against cancer cell lines A549, HeLa, HCT-116, and MDA-MB-231 in the submicromolar concentration range. Structure-activity relationship (SAR) studies on a range of derivatives aided in identifying key pharmacophores in the lead compound. A series of compounds have been identified as the most promising with submicromolar IC50 values against a lung cancer cell line (A549). Microscopy studies of cancer cells treated with the lead compound revealed that it causes mitotic arrest and disrupts microtubules. Further evaluation via an in vitro microtubule polymerization assay and competition studies indicate that the lead compound binds to tubulin via the colchicine site.

The Recent Development of Tetrahydro-Quinoline/Isoquinoline Based Compounds as Anticancer Agents.

Tetrahydroquinoline and isoquinoline scaffolds are important class of heterocyclic compounds, which is implied for the development of new drugs and diagnostic for therapeutic function. Naturally occurring as well as synthetic tetrahydroquinolines/isoquinolines possess many different biological activities and have been testified as remarkable cytotoxic and potency in human cancer cell lines. Tetrahydroquinoline/isoquinoline based compounds displayed a key role in the development of anticancer drugs or lead molecules and acting through various mechanisms such as cell proliferation, apoptosis, DNA fragmentation, inhibition of tubulin polymerization, induced cell cycle arrest, interruption of cell migration, and modulation. The number of tetrahydroquinoline/isoquinoline derivatives has been reported as potent anticancer agents. Due to promising anticancer activities and wideranging properties of these molecules, we have compiled the literature for the synthesis and anticancer properties of various tetrahydroquinolines and isoquinolines. We have reported the synthesis of potent tetrahydroquinoline/isoquinoline molecules of the last 10 years with their anticancer properties in various cancer cell lines and stated their half-maximal inhibitory concentration (IC50). In addition, we also considered the discussion of molecular docking and structural activity relationship wherever provided to understand the possible mode of activity a target involved and structural feature responsible for the better activity, so the reader can directly find the detail for designing new anticancer agents.

Synthesis and Biological Screening of New Cyano-Substituted Pyrrole Fused (Iso)Quinoline Derivatives.

Several new cyano-substituted derivatives with pyrrolo[1,2-a]quinoline and pyrrolo[2,1-a]isoquinoline scaffolds were synthesized by the [3 + 2] cycloaddition of (iso)quinolinium ylides to fumaronitrile. The cycloimmonium ylides reacted in situ as 1,3-dipoles with fumaronitrile to selectively form distinct final compounds, depending on the structure of the (iso)quinolinium salt. Eleven compounds were evaluated for their anticancer activity against a panel of 60 human cancer cell lines. The most potent compound 9a showed a broad spectrum of antiproliferative activity against cancer cell lines representing leukemia, melanoma and cancer of lung, colon, central nervous system, ovary, kidney, breast and prostate cancer. In vitro assays and molecular docking revealed tubulin interaction properties of compound 9a.