Synthetic Medicinal Chemistry Research Articles

Nucleobase-modified nucleosides and nucleotides: Applications in biochemistry, synthetic biology, and drug discovery.

. DNA is often referred to as the "molecule of life" since it contains the genetic blueprint for all forms of life on this planet. The core building blocks composing DNA are deoxynucleotides. While the deoxyribose sugar and phosphate group are ubiquitous, it is the composition and spatial arrangement of the four natural nucleobases, adenine (A), cytosine (C), guanine (G), and thymine (T), that provide diversity in the coding information present in DNA. The ability of DNA to function as the genetic blueprint has historically been attributed to the formation of proper hydrogen bonding interactions made between complementary nucleobases. However, recent chemical and biochemical studies using nucleobase-modified nucleotides that contain "non-hydrogen bonding" functional groups have challenged many of the dogmatic views for the necessity of hydrogen-bonding interactions for DNA stability and function. Based on years of exciting research, this area has expanded tremendously and is thus too expansive to provide a comprehensive review on the topic. As such, this review article provides an opinion highlighting how nucleobase-modified nucleotides are being applied in diverse biomedical fields, focusing on three exciting areas of research. The first section addresses how these analogs are used as mechanistic probes for DNA polymerase activity and fidelity during replication. This section outlines the synthetic logic and medicinal chemistry approaches used to replace hydrogen-bonding functional groups to examine the contributions of shape/size, nucleobase hydrophobicity, and pi-electron interactions. The second section extends these mechanistic studies to provide insight into how nucleobase-modified nucleosides are used in synthetic biology. One example is through expansion of the genetic code in which changing the composition of DNA makes it possible to site-specifically incorporate unnatural amino acids bearing unique functional groups into enzymes and receptors. The final section describes results of pre-clinical studies using nucleobase-modified nucleosides as potential therapeutic agents against diseases such as cancer.

DBU Promoted Polysubstituted Arene Formation via a Michael Addition/Cyclization/Elimination Cascade Reaction

The straightforward construction of polysubstituted arenes is essential in both synthetic chemistry and medicinal chemistry. Herein, we reported a DBU promoted Michael addition/cyclization/elimination cascade reaction between vinylogous malononitrile derivatives and chlorinated nitrostyrenes for the synthesis of polysubstituted arenes. The method features mild reaction conditions, wide substrate scope and high yield. Interestingly, preliminary study of the enantioselective version of this cascade was conducted to give chiral biaryl atropisomers with up to 40% ee through center-to-axial chirality transfer strategy.

Understanding the Nature and Strength of Noncovalent Face‐to‐Face Arene–Fullerene Interactions

AbstractFace‐to‐face noncovalent arene−fullerene interactions are important in several research fields such as synthetic chemistry, materials chemistry, and medicinal chemistry; however, their nature and strength are still poorly understood. In this study, we prepare a fullerene‐based torsion balance containing thioanisole, phenol, naphthalene, azulene, and pyrene moieties as a unimolecular model system. Moreover, we compare the folding free energies between the folded and the unfolded conformers of a series of the molecular torsion balances to quantify noncovalent interactions between arenes and the fullerene surface. This work demonstrates that the contributions of polarizabilities, anionic charges, electronic dipole moments, and the number of arene rings to the interactions can be experimentally measured by analyzing the folding equilibrium of the molecular torsion balances.

Understanding the Nature and Strength of Noncovalent Face-to-Face Arene-Fullerene Interactions.

Face-to-face noncovalent arene-fullerene interactions are important in several research fields such as synthetic chemistry, materials chemistry, and medicinal chemistry; however, their nature and strength are still poorly understood. In this study, we prepare a fullerene-based torsion balance containing thioanisole, phenol, naphthalene, azulene, and pyrene moieties as a unimolecular model system. Moreover, we compare the folding free energies between the folded and the unfolded conformers of a series of the molecular torsion balances to quantify noncovalent interactions between arenes and the fullerene surface. This work demonstrates that the contributions of polarizabilities, anionic charges, electronic dipole moments, and the number of arene rings to the interactions can be experimentally measured by analyzing the folding equilibrium of the molecular torsion balances.

Visible-Light-Induced [4+1] Cyclization-Aromatization of Acylsilanes and α,β-Unsaturated Ketones

Visible-Light-Induced [4+1] Cyclization-Aromatization of Acylsilanes and α,β-Unsaturated Ketones

Recent Developments in Nucleophilic Fluorination with Potassium Fluoride (KF): A Review

AbstractFluorinated compounds act as a link between synthetic organic chemistry and medicinal chemistry and compel researchers to explore modified and innovative methods for the syntheses of fluorinated motifs. The identification of reliable and efficient methods for the fluorination of organic moieties remains a major challenge in synthetic organic chemistry. Nucleophilic fluorination reactions using a combination of potassium fluoride (KF) and various catalysts or promoters emerged as a viable strategy and provided access to versatile organofluorine compounds. This review will emphasize recent advancements in nucleophilic fluorination reactions using KF: aliphatic nucleophilic fluorination, aromatic nucleophilic fluorination, and heteroatomic nucleophilic fluorination with ionic liquids, modified crown ethers, and transition metal‐catalysts in various protic and aprotic media.

Transition Metal-Catalyzed Regioselective Direct C-H Amidation: Interplay between Inner- and Outer-Sphere Pathways for Nitrene Cross-Coupling Reactions.

Catalytic C-N bond cross-coupling reactions have been a subject of fundamental importance in synthetic organic and medicinal chemistry because amides and amines are ubiquitous motifs in natural products, functional materials, and pharmaceuticals. Since the pioneering works of Breslow and Mansuy on the metalloporphyrin-catalyzed direct hydrocarbon amidation using sulfonyliminoiodinane reagents, substantial development has been achieved toward practical and selective amination protocols. Notably, Du Bois's group developed the dirhodium(II,II) carboxylate catalytic system for direct C(sp3)-H amidations via Rh-sulfonyl nitrene intermediates. Yet, this protocol suffers from competitive alkene aziridination and is limited to electron-rich tertiary and ethereal C-H bonds; analogous direct amidation of arenes remained ineffective.This Account discusses our early effort to explore cyclopalladated complexes for ortho-selective C(aryl)-H amidations. While Buchwald-Hartwig amination cannot be directly applied to arenes, effective amidation of the 2-arylpyridines occurred when an external oxidant such as K2S2O8 was employed. Preliminary studies suggested that the amidation may proceed through reactive Pd-nitrene intermediates. Aiming to develop more diversified amidation protocols, we employed nosyloxycarbamates as nitrene precursors for the Pd-catalyzed ortho-amidation of N-pivalanilides. Likewise, we developed the ortho-selective amidation of benzoic acids to produce anthranilic acids, which are versatile precursors for many medicinally valuable heterocycles. In an attempt to expand the C(aryl)-N coupling reactions to amines, we studied the d6 piano-stool Cp*Rh(III) systems [Cp* = pentamethylcyclopentadienyl]. Our work established a sound reaction platform based on the electrophilic aminating reagents including N-chloroamines, hydroxyamides, and N-carboxyhydrazides for effective C(aryl)-N bond formation in aryl-metal complexes.Building upon the metal-nitrene reaction platform, we moved forward to examine γ-lactam synthesis by intramolecular carbonyl nitrene C(sp3)-H insertion. Noted that carbonyl nitrenes are prone to undergo Curtius-type rearrangement to form isocyanate; we found that the π-basic Ru(II) center effectively decomposes dioxazolones to afford the carbonyl nitrene for regioselective γ-C(sp3)-H insertion. With chiral diphenylethylenediamines (dpen) as ligands bearing electron-withdrawing arylsulfonyl substituents, the [(p-cymene)Ru(dpen)] complex catalyzed the decomposition of the dioxazolones to afford chiral γ-lactams by formal carbonyl nitrene C(sp3)-H insertion. Enantioselective nitrene insertion to allylic and propargylic C(sp3)-H bonds was also achieved with remarkable tolerance to the C═C and C≡C bonds. Notably, the selectivity of the [(p-cymene)Ru] system switched to C(aryl)-H bonds to give dihydroquinolinones when l-proline was employed as ligand. Recently, we aimed to address the regiocontrolled amidation of unactivated methylene C-H bonds using NiH catalyst. While tertiary and benzyl C-H bonds can be differentiated by their bond dissociation energies and steric properties, methylene groups making up the hydrocarbon skeleton display similar electronic and steric properties. In this context, we exploited the five-membered nickelacycle formation to terminate the NiH-mediated chain-walk isomerization, and the nickelacycle reacted with dioxazolones to furnish the C(sp3)-N bond at the γ-methylene position.This Account summarizes our contribution to the development of C-N bond cross-coupling reactions via C-H activation. By exploiting the inner-sphere and outer-sphere reaction pathways, we successfully developed regioselective protocols that target C(sp3)-H and C(aryl)-H bonds. The mechanistic underpinning of the selectivity of different C-H bonds and related studies on the affiliated catalytic systems will be discussed.

Abstract 6366: A novel small molecule inhibitor of MAPK and PI3K ameliorates disease phenotypes in myelofibrosis

Abstract Myelofibrosis is a myeloproliferative neoplasm (MPN) caused primarily by mutations in hematopoietic stem and progenitor cells (HSPCs) that activate Janus kinase 2 (JAK2). Central roles for JAK2 signaling in myelofibrosis (MF) have been established, leading to marked extramedullary hematopoiesis, splenomegaly, and bone marrow fibrosis, but the use of JAK inhibitors has shown limited ability to produce durable remissions in most patient populations. Bypass or resistance mechanisms to JAK inhibition have been linked to concomitant activation of compensatory phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways, and while genetic and functional studies have not fully defined the mechanisms for transformation and maintenance of the proliferative state in MF, targeting multiple signaling pathways will be required to alter the disease course and improve therapeutic outcomes. Treatments using kinase inhibitor combinations remain a challenge clinically, and trials have struggled to create positive balance between gains in survival, therapeutic efficacy, and dose-limiting toxicity. A multi-functional kinase inhibitor was developed to deliver consistent and synergistic dosing ratios against multiple targets simultaneously, thereby blocking compensatory oncogenic signaling pathways while minimizing the prospect for adverse effects. Using synthetic medicinal chemistry, we present a potent and selective, orally bioavailable, single-molecule multi-targeted kinase inhibitor (LP-182) against MAPK and PI3K/mTOR signaling pathways. We demonstrate selectivity and therapeutic efficacy through in vitro screening of kinome inhibition, reduction of cell growth and downstream kinase activation, renormalization of immune cell populations, amelioration of splenomegaly and bone marrow fibrosis, and improved survival in the myeloproliferative leukemia oncogene (MPLW515L) mouse model of myelofibrosis. Furthermore, treatment with LP-182 was well tolerated showing no observable pharmacotoxicity, and combination with the JAK inhibitor Ruxolitinib also showed ~35% reduction in spleen size as compared to either treatment alone with a ~60% spleen volume reduction compared to vehicle treatment, in the JAK2+/V617F mutant mouse model. Overall, these data suggest that in vivo bioavailability and distribution of LP-182 to secondary lymphoid tissues attenuates MAPK and PI3K signaling to alleviate disease phenotypes in animal models of MF. Simultaneous targeting of both MAPK and PI3K pathways with LP-182 alone or in combination with JAK inhibition provides the potential for significant new opportunities to improve the clinical outcome of MF patients. Citation Format: Christopher A. Bonham, Youngsoon Jang, Kevin Heist, Amanda Welton, Tanner Robison, Kathryn E. Luker, Gary D. Luker, Winston Y. Lee, Thomas L. Chenevert, Marcian Van Dort, Brian D. Ross. A novel small molecule inhibitor of MAPK and PI3K ameliorates disease phenotypes in myelofibrosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6366.

Replacement of Less-Preferred Dipolar Aprotic and Ethereal Solvents in Synthetic Organic Chemistry with More Sustainable Alternatives.

Dipolar aprotic and ethereal solvents comprise just over 40% of all organic solvents utilized in synthetic organic, medicinal, and process chemistry. Unfortunately, many of the common “go-to” solvents are considered to be “less-preferable” for a number of environmental, health, and safety (EHS) reasons such as toxicity, mutagenicity, carcinogenicity, or for practical handling reasons such as flammability and volatility. Recent legislative changes have initiated the implementation of restrictions on the use of many of the commonly employed dipolar aprotic solvents such as dimethylformamide (DMF) and N-methyl-2-pyrrolidinone (NMP), and for ethers such as 1,4-dioxane. Thus, with growing legislative, EHS, and societal pressures, the need to identify and implement the use of alternative solvents that are greener, safer, and more sustainable has never been greater. Within this review, the ubiquitous nature of dipolar aprotic and ethereal solvents is discussed with respect to the physicochemical properties that have made them so appealing to synthetic chemists. An overview of the current legislative restrictions being imposed on the use of dipolar aprotic and ethereal solvents is discussed. A variety of alternative, safer, and more sustainable solvents that have garnered attention over the past decade are then examined, and case studies and examples where less-preferable solvents have been successfully replaced with a safer and more sustainable alternative are highlighted. Finally, a general overview and guidance for solvent selection and replacement are included in the Supporting Information of this review.

Selenium-Based Fluorescence Probes for the Detection of Bioactive Molecules.

Chemistry of organoselenium reagents have now become an important tool of synthetic organic and medicinal chemistry. These reagents activate the olefinic double bonds and used to archive the number of organic transformations under mild reaction conditions. A number of organoselenium compounds have been identified as potent oxidants. Recently, various organoselenium species have been employed as chemical sensors for detecting toxic metals. Moreover, a number of selenium-based fluorescent probes have been developed for detecting harmful peroxides and ROS. In this review article, the synthesis of selenium-based fluorescent probes will be covered including their application in the detection of toxic metals and harmful peroxides including ROS.

Amide Bonds Meet Flow Chemistry: A Journey into Methodologies and Sustainable Evolution.

Formation of amide bonds is of immanent importance in organic and synthetic medicinal chemistry. Its presence in “traditional” small‐molecule active pharmaceutical ingredients, in linear or cyclic oligo‐ and polypeptidic actives, including pseudopeptides, has led to the development of dedicated synthetic approaches for the formation of amide bonds starting from, if necessary, suitably protected amino acids. While the use of solid supported reagents is common in traditional peptide synthesis, similar approaches targeting amide bond formation in continuous‐flow mode took off more significantly, after a first publication in 2006, only a couple of years ago. Most efforts rely upon the transition of traditional approaches in flow mode, or the combination of solid‐phase peptide synthesis principles with flow chemistry, and advantages are mainly seen in improving space‐time yields. This Review summarizes and compares the various approaches in terms of basic amide formation, peptide synthesis, and pseudopeptide generation, describing the technological approaches and the advantages that were generated by the specific flow approaches. A final discussion highlights potential future needs and perspectives in terms of greener and more sustainable syntheses.

Transition metal-catalyzed double Cvinyl-H bond activation: synthesis of conjugated dienes.

Conjugated dienes have occupied a pivotal position in the field of synthetic organic chemistry and medicinal chemistry. They act as important synthons for the synthesis of various biologically important molecules and therefore, gain tremendous attention worldwide. A wide range of synthetic routes to access these versatile molecules have been developed in the past decades. Transition metal-catalyzed cross-dehydrogenative coupling (CDC) has emerged as one of the utmost front-line research areas in current synthetic organic chemistry due to its high atom economy, efficiency, and viability. In this review, an up-to-date summary including scope, limitations, mechanistic studies, stereoselectivities, and synthetic applications of transition metal-catalyzed double Cvinyl-H bond activation for the synthesis of conjugated dienes has been reported since 2013. The literature reports mentioned in this review have been classified into three different categories, i.e. (a) Cvinyl-Cvinyl bond formation via oxidative homo-coupling of terminal alkenes; (b) Cvinyl-Cvinyl bond formation via non-directed oxidative cross-coupling of linear/cyclic alkenes and terminal/internal alkenes, and (c) Cvinyl-Cvinyl bond formation via oxidative cross-coupling of directing group bearing alkenes and terminal/internal alkenes. Overall, this review aims to provide a concise overview of the current status of the considerable development in this field and is expected to stimulate further innovation and research in the future.

Microwave-assisted C-C, C-O, C-N, C-S Bond Formation and Multicomponent Reactions Using Magnetic Retrievable Nanocatalysts

Microwave-assisted organic synthesis has been perceived as one of the most powerful and sustainable tools to accomplish expeditious organic synthesis through a greener way on account of its specific features, including targeted heating, reaction homogeneity, rapidity, possible modifications of activation parameters, improved selectivity, yield and purity, along with simpler work-up. Another rapidly growing field for the development of the green and sustainable protocol is the application of magnetic nanocatalysts. They not only meet the need for facile recovery from the reaction media after completion of a reaction but also provide the best attributes of nanotechnology along with the elimination of auxiliary substances and catalyst loss, thereby making the overall process clean, fast and cost-effective. Thus, the amalgamation of magnetic nanocatalysts and microwave irradiation presents an ideal blend for the development of sustainable methods in synthetic organic chemistry. Amidst various bond forming reactions, carbon-carbon (C-C) and carbon- heteroatom (C-X, where X= O, N, S) bond formations are essentially used to devise privileged molecular scaffolds for synthetic organic and medicinal chemistry. This review gives a succinct overview of the synthesis and application of various modified magnetic nanocomposites as taskspecific catalysts for microwave assisted C-C and C-X bond formation reactions in recent years.

Insight View on Synthetic Strategies and Biological Applications of Pyrimidobenzothiazoles

: Pyrimidobenzothiazoles and its derivatives are important structural scaffolds in the field of synthetic organic chemistry and medicinal chemistry. The review is focused on one pot multicomponent approaches for generating pyrimidobenzothiazoles and its derivatives along with their interesting biological profile over the last ten years. Several eco-benign and cost effective approaches such as nano catalyst, ionic liquid, metal, solid acid, catalyst free, solvent free, etc. for its synthesis have been discussed in this review. Different synthetic strategies of pyrimidobenzothiazole derivatives have been compiled and discussed using 2-aminobenzothiazole, 1,3 diketones, substituted aldehydes, alkynoic acid, bis-methyl thiomethylene malononitrile, Baylis Hillman acetates, etc.

Ugi Adducts of Isatin as Promising Antiproliferative Agents with Druglike Properties

AbstractMulticomponent reactions (MCRs) are a valuable tool for the sustainable synthesis of new molecules in a fast, effective and eco‐friendly manner, leading to the generation of structurally diverse libraries. Their application in synthetic organic chemistry and medicinal chemistry, in combination with privileged scaffolds, is gaining momentum in recent years. The Ugi reaction is one of the most widely used MCRs in medicinal chemistry, and it is even used for the synthesis of several active pharmaceutical ingredients. Isatin, known for its biological activities and synthetic versatility, has been vastly used in several MCRs, however it was rarely used in combination with the Ugi reaction. Herein we report the first library of isatin‐based Ugi 4 component reaction (U4CR) derivatives. Reaction optimization and scope were thoroughly explored, as well as mechanistic insights were obtained using DFT calculations. The resulting library was evaluated in what concerns its druglike properties, pharmacokinetic profile assessment in silico and antiproliferative activity in vitro, with several compounds bearing interesting druglike properties. Biological screening against six tumor cell lines, showed that the majority of the compounds display antiproliferative activity in the low and sub‐micromolar range, with the achievement of nanomolar activity (0.1 nM, 6.5 nM and 5.4 nM against HBL‐100, HeLa and WiDr, respectively) for the more active compound.

Exploration of Pyrazolo[1,5-a]pyrimidines as Membrane-Bound Pyrophosphatase Inhibitors.

Inhibition of membrane‐bound pyrophosphatase (mPPase) with small molecules offer a new approach in the fight against pathogenic protozoan parasites. mPPases are absent in humans, but essential for many protists as they couple pyrophosphate hydrolysis to the active transport of protons or sodium ions across acidocalcisomal membranes. So far, only few nonphosphorus inhibitors have been reported. Here, we explore the chemical space around previous hits using a combination of screening and synthetic medicinal chemistry, identifying compounds with low micromolar inhibitory activities in the Thermotoga maritima mPPase test system. We furthermore provide early structure‐activity relationships around a new scaffold having a pyrazolo[1,5‐a]pyrimidine core. The most promising pyrazolo[1,5‐a]pyrimidine congener was further investigated and found to inhibit Plasmodium falciparum mPPase in membranes as well as the growth of P. falciparum in an ex vivo survival assay.

Construction of Si‐Stereogenic Silanes through C−H Activation Approach

AbstractThe asymmetric synthesis of Si‐stereogenic silanes has attracted great attention due to the increasing values of Si‐containing functional molecules in synthetic chemistry, medicinal chemistry, and material chemistry. Merging organosilicon chemistry with transition‐metal‐catalyzed C−H approach has led to rich sets of new reactions holding great synthetic values. This Minireview aims to summarize the advances in the construction of Si‐stereogenic silanes through the transition‐metal‐catalyzed C−H activation approach.

Hydroxamic Acid Derivatives: From Synthetic Strategies to Medicinal Chemistry Applications.

Since the approval of three hydroxamic acid-based HDAC inhibitors as anticancer drugs, such functional groups acquired even more notoriety in synthetic medicinal chemistry. The ability of hydroxamic acids (HAs) to chelate metal ions makes this moiety an attractive metal binding group—in particular, Fe(III) and Zn(II)—so that HA derivatives find wide applications as metalloenzymes inhibitors. In this minireview, we will discuss the most relevant features concerning hydroxamic acid derivatives. In a first instance, the physicochemical characteristics of HAs will be summarized; then, an exhaustive description of the most relevant methods for the introduction of such moiety into organic substrates and an overview of their uses in medicinal chemistry will be presented.

Significance of 1,3,4-Oxadiazole Containing Compounds in New Drug Development.

Oxadiazole core displays various pharmacological properties among five membered nitrogen heterocyclic compounds, specially 1,3,4-oxadiazole containing molecules that have occupied a particular place in the field of synthetic medicinal chemistry as surrogates (bioisosteres) of carboxylic acids, carboxamides and esters. Moreover, they are having widespread kind of applications in numerous zones as polymers, as luminescence producing materials and as electron- transporting materials and corrosion inhibitors. This study contains comprehensive and extensive literature survey on chemical reactivity and biological properties associated with 1,3,4-oxadiazole containing compounds. This review summarises 1,3,4-oxadiazole moiety in numerous compounds with reported pharmacological activity such as antiviral, analgesic and anti-inflammatory, antitumor, antioxidant, insecticidal and anti-parasitic, etc. Nevertheless, ring opening reactions of the 1,3,4-oxadiazole core have also made great attention, as they produce new analogues containing an aliphatic nitrogen atom and to other ring systems. In relation to the occurrence of oxadiazoles in biologically active molecules, 1,3,4- oxadiazole core emerges as a structural subunit of countless significance and usefulness for the development of new drug aspirants applicable to the treatment of many diseases. It concludes that 1,3,4-oxadiazole core compounds are more efficacious and less toxic medicinal agents with respect to new opinions in the search for rational strategies.

A Computational Study of Asymmetric Hydrogenation of 2‐Phenyl Acrylic Acids Catalyzed by a Rh(I) Catalyst with Ferrocenyl Chiral Bisphosphorus Ligand: The Role of Ion‐Pair Interaction†

Main observation and conclusionAsymmetric hydrogenation reaction is one of the most efficient synthetic methods to form useful chiral compounds for synthetic chemistry, medicinal chemistry and material chemistry. Generally, the enantioselectivity of many hydrogenation reactions is controlled by steric hindrance between the chiral ligand and substrate. Recently, Zhang group developed a highly asymmetric hydrogenation of 2‐aryl and 2‐alkyl acrylic acids catalyzed by a Rh(I) catalyst with a chiral Wudaphos ligand. The excellent enantioselectivity of this asymmetric reaction was proposed to be controlled by ion‐pair interaction between the substrate and chiral ligand. In this study, a systematic density functional theory study has been carried out to investigate the reaction mechanism and origin of the enantioselectivity. Our computational results suggest that this reaction follows the classic mechanism involving oxidative addition of H2, migratory insertion and reductive elimination. Different from the C=C coordination to the metal in the common oxidative addition step, our study found that the chelation of the carboxyl group of the substrate to the cationic Rh(I) metal is more favorable in this oxidative addition step. The high enantioselectivity is proposed to be dictated by a better catalyst/substrate geometric complementarity in the major pathway to have less distortion of the catalyst for a strong ion‐pair interaction.