In vivo Structure-Activity Relationship of Dihydromethysticin in Reducing Nicotine-Derived Nitrosamine Ketone (NNK)-Induced Lung DNA Damage against Lung Carcinogenesis in A/J Mice.

Lung cancer is the leading cause of cancer-related deaths and chemoprevention should be developed. We recently identified dihydromethysticin (DHM) as a promising candidate to prevent NNK-induced lung tumorigenesis. To probe its mechanisms and facilitate its future translation, we investigated the structure-activity relationship of DHM on NNK-induced DNA damage in A/J mice. Twenty DHM analogs were designed and synthesized. Their activity in reducing NNK-induced DNA damage in the target lung tissues was evaluated. The unnatural enantiomer of DHM was identified to be more potent than the natural enantiomer. The methylenedioxy functional moiety did not tolerate modifications while the other functional groups (the lactone ring and the ethyl linker) accommodated various modifications. Importantly, analogs of high structural similarity to DHM with distinct efficacy in reducing NNK-induced DNA damage have been identified. They will serve as chemical probes to elucidate the mechanisms of DHM in blocking NNK-induced lung carcinogenesis.

AZD5438-PROTAC: A selective CDK2 degrader that protects against cisplatin- and noise-induced hearing loss.

Cyclin-dependent kinase 2 (CDK2) is a potential therapeutic target for the treatment of hearing loss and cancer. Previously, we identified AZD5438 and AT7519-7 as potent inhibitors of CDK2, however, they also targeted additional kinases, leading to unwanted toxicities. Proteolysis Targeting Chimeras (PROTACs) are a new promising class of small molecules that can effectively direct specific proteins to proteasomal degradation. Herein we report the design, synthesis, and characterization of PROTACs of AT7519-7 and AZD5438 and the identification of PROTAC-8, an AZD5438-PROTAC, that exhibits selective, partial CDK2 degradation. Furthermore, PROTAC-8 protects against cisplatin ototoxicity and kainic acid excitotoxicity in zebrafish. Molecular dynamics simulations reveal the structural requirements for CDK2 degradation. Together, PROTAC-8 is among the first-in-class PROTACs with in vivo therapeutic activities and represents a new lead compound that can be further developed for better efficacy and selectivity for CDK2 degradation against hearing loss and cancer.

Characterization of quinoxaline derivatives for protection against iatrogenically induced hearing loss.

Hair cell loss is the leading cause of hearing and balance disorders in humans. It can be caused by many factors, including noise, aging, and therapeutic agents. Previous studies have shown the therapeutic potential of quinoxaline against drug-induced ototoxicity. Here, we screened a library of 68 quinoxaline derivatives for protection against aminoglycoside-induced damage of hair cells from the zebrafish lateral line. We identified quinoxaline-5-carboxylic acid (Qx28) as the best quinoxaline derivative that provides robust protection against both aminoglycosides and cisplatin in zebrafish and mouse cochlear explants. FM1-43 and aminoglycoside uptake, as well as antibiotic efficacy studies, revealed that Qx28 is neither blocking the mechanotransduction channels nor interfering with aminoglycoside antibacterial activity, suggesting that it may be protecting the hair cells by directly counteracting the ototoxin's mechanism of action. Only when animals were incubated with higher doses of Qx28 did we observe a partial blockage of the mechanotransduction channels. Finally, we assessed the regulation of the NF-κB pathway in vitro in mouse embryonic fibroblasts and in vivo in zebrafish larvae. Those studies showed that Qx28 protects hair cells by blocking NF-κB canonical pathway activation. Thus, Qx28 is a promising and versatile otoprotectant that can act across different species and toxins.

Transcriptome analysis predicts mode of action of benzimidazole molecules against Staphylococcus aureus UAMS-1.

Antimicrobial drug resistance is one of the most critical problems that plagued the human race in modern times. Discovery of novel antibiotics is important to counter this threat. Accordingly, herein we have reported the discovery of substituted benzimidazole class of molecules with antimicrobial property (specifically against Staphylococcus aureus). They were initially identified through a random screening and a novel catalytic synthetic strategy was utilized to access them. in vitro screening and phenotypic profiling revealed the antimicrobial nature. De novo transcriptome and gene analyses predicted the putative targets. This work provides a solid foundation for developing the benzimidazoles as a target specific antimicrobial preclinical candidate.

Exploring the Structure-Activity Relationship and Mechanism of a Chromene Scaffold (CXL Series) for Its Selective Antiproliferative Activity toward Multidrug-Resistant Cancer Cells.

Multidrug resistance (MDR) is one major barrier in cancer management, which urges for new drugs to help treat MDR malignancies and elucidate MDR mechanisms. A series of chromene compounds (the CXL series) demonstrate increased antiproliferative activity toward MDR acute-myeloid-leukemia (AML) cells. The structure-activity relationship (SAR) of the antiproliferative potency has been partly characterized, whereas the structural determinants contributing to selectivity have not been investigated. In this study, three series of CXL compounds were synthesized and evaluated in HL60 and HL60/MX2 leukemia cells. The results not only confirmed previous SAR studies but also, for the first time, provided structural insights into the selectivity for MDR HL60/MX2 cells. Using the lead compounds as probes, we demonstrated that their modulation of intracellular-calcium homeostasis results in their antiproliferative potency and selectivity. Three candidates also demonstrate excellent in vitro safety profiles between cancer cells and normal cells, which will be evaluated in vivo in future studies.

Oxidative dehydrogenation of C-C and C-N bonds: A convenient approach to access diverse (dihydro)heteroaromatic compounds.

Nitrogen heteroarenes form an important class of compounds which can be found in natural products, synthetic drugs, building blocks etc. Among the diverse strategies that were developed for the synthesis of nitrogen heterocycles, oxidative dehydrogenation is extremely effective. This review discusses various oxidative dehydrogenation strategies of C-C and C-N bonds to generate nitrogen heteroarenes from their corresponding heterocyclic substrates. The strategies are categorized under stoichiometric and catalytic usage of reagents that facilitate such transformations. The application of these strategies in the synthesis of nitrogen heteroarene natural products and synthetic drug intermediates are also discussed. We hope this review will arouse sufficient interest among the scientific community to further advance the application of oxidative dehydrogenation in the synthesis of nitrogen heteroarenes.

A novel spiroindoline targets cell cycle and migration via modulation of microtubule cytoskeleton.

Natural product-inspired libraries of molecules with diverse architectures have evolved as one of the most useful tools for discovering lead molecules for drug discovery. In comparison to conventional combinatorial libraries, these molecules have been inferred to perform better in phenotypic screening against complicated targets. Diversity-oriented synthesis (DOS) is a forward directional strategy to access such multifaceted library of molecules. From a successful DOS campaign of a natural product-inspired library, recently a small molecule with spiroindoline motif was identified as a potent anti-breast cancer compound. Herein we report the subcellular studies performed for this molecule on breast cancer cells. Our investigation revealed that it repositions microtubule cytoskeleton and displaces AKAP9 located at the microtubule organization centre. DNA ladder assay and cell cycle experiments further established the molecule as an apoptotic agent. This work further substantiated the amalgamation of DOS-phenotypic screening-sub-cellular studies as a consolidated blueprint for the discovery of potential pharmaceutical drug candidates.

Spiro[pyrrolidine-3, 3´-oxindole] as potent anti-breast cancer compounds: Their design, synthesis, biological evaluation and cellular target identification.

The spiro[pyrrolidine-3, 3´-oxindole] moiety is present as a core in number of alkaloids with substantial biological activities. Here in we report design and synthesis of a library of compounds bearing spiro[pyrrolidine-3, 3´-oxindole] motifs that demonstrated exceptional inhibitory activity against the proliferation of MCF-7 breast cancer cells. The synthesis involved a one pot Pictet Spengler-Oxidative ring contraction of tryptamine to the desired scaffolds and occurred in 1:1 THF and water with catalytic trifluoroacetic acid and stoichiometric N-bromosuccinimide as an oxidant. Phenotypic profiling indicated that these molecules induce apoptotic cell death in MCF-7 cells. Target deconvolution with most potent compound 5l from the library, using chemical proteomics indicated histone deacetylase 2 (HDAC2) and prohibitin 2 as the potential cellular binding partners. Molecular docking of 5l with HDAC2 provided insights pertinent to putative binding interactions.

Accessing Benzimidazoles via a Ring Distortion Strategy: An Oxone Mediated Tandem Reaction of 2-Aminobenzylamines.

An exceptional oxone mediated tandem transformation of 2-aminobenzylamines to 2-substituted benzimidazoles is reported. It occurs at room temperature with aromatic, heteroaromatic, and aliphatic aldehydes. In this reaction initial condensation of 2-aminobenzylamine with appropriate aldehydes afforded a tetrahydroquinazoline intermediate which underwent oxone-mediated ring distortion to afford the desired compounds in moderate to excellent yields.

Innovative techniques to discover novel antimalarials.

Malaria a global pandemic has engulfed nearly 0.63 million people globally. It is high time that a cure for malaria is required to stop its ever increasing menace. Our commentary discusses the advent and contribution of genetic algorithm (GA) in the drug discovery efforts towards developing cure for malaria. GAs are computational models of Darwinian evolution, ideally capture and mimic the principles of genetic variation and natural selection to evolve good solutions through multiple iterations on the space of all possible candidate solutions, called the search space, to a given optimization problem. Herein we will discuss the applications, advantages, disadvantages and future directions of GA with respect to malaria.

Design, synthesis and evaluation of thiohydantoin derivatives as potent topoisomerase I (Top1) inhibitors with anticancer activity.

DNA topoisomerase I is a potential chemotherapeutic target. Here, we designed and synthesized a library comprising of hydantoin and thiohydantoin derivatives and tested them against human and Leishmania Top1. One of the thiohydantoin compounds with substituted thiophenyl as the central moiety (compound 15) exhibited potent inhibition of human Top1 (HTop1) through stabilization of Top1-DNA cleavage complexes and showed selective anticancer activity against human cervical carcinoma (HeLa) and breast carcinoma (MCF-7) cell lines. Molecular modeling studies with HTop1 rationalized the inhibitory mechanism of compound 15.

Design, synthesis and biological evaluation of small molecules as potent glucosidase inhibitors.

Herein we have reported design, synthesis and in vitro biological evaluation of a library of bicyclic lactams that led to the discovery of compounds 6 and 7 as a novel class of α-glucosidase inhibitors. They inhibited α-glucosidase (yeast origin) in a mixed type of inhibition with an IC50 of ∼150 nM. Molecular docking studies further substantiated screening results. Interestingly phenotypic screening of this library against the human malaria parasite revealed 7 as a potent antiplasmodial agent.