MEK inhibitors in oncology: a patent review and update (2016 - present).

INTRODUCTION: Mitogen-activated protein kinase (MEK) is one of the important components of Ras/Raf/MEK/ERK signaling pathway, transduces signal for cell growth, differentiation, and development. Deregulation of MEK leads to a wide variety of cancer; hence, MEK is considered as potential therapeutic targets for the treatment of cancer. The MEK1/2 inhibitors in combination with other inhibitors showed better therapeutic outcomes in various malignancies including resistant or relapsed or refractory cancer. AREAS COVERED: A comprehensive patent literature from the year 2016 to May 2024 on MEK inhibitors in oncology, their combination products and structural insights have been reviewed through searching relevant information in PubMed, Scopus, Espacenet, Web of Science, World Intellectual Property Organization and Google Patent databases. EXPERT OPINION: Overexpression and mutation of MEK have been reported to cause a wide variety of cancers especially resistant cancers. The MEK1/2 inhibitors in combination with other kinase (BRaf/KRas/PI3K) inhibitors showed significant anti-proliferative activity. Other combination of MEK inhibitor with PD-1, DYRK1, EGFR, BTK and/or VEGF inhibitors, etc. showed promising results in many cancers including colorectal, pancreatic, gastrointestinal, solid tumor, breast cancer, melanoma and multiple myeloma, etc. The dual or multi-targeted approaches of these combinations showed better and precise treatment of patients with resistant cancer.

PIM kinase inhibitors: an updated patent review (2016-present).

INTRODUCTION: PIM Kinases (PIM-1, PIM-2, and PIM-3) have been reported to play crucial role in signaling cascades that govern cell survival, proliferation, and differentiation. Over-expression of these kinases leads to hematological malignancies such as diffuse large B cell lymphomas (DLBCL), multiple myeloma, leukemia, lymphoma and prostate cancer etc. PIM kinases as biomarkers and potential therapeutic targets have shown promise toward precision cancer therapy. The selective PIM-1, PIM-2, and/or PIM-3 isoform inhibitors have shown significant results in patients with advanced stages of cancer including relapsed/refractory cancer. AREAS COVERED: A comprehensive literature review of PIM Kinases (PIM-1, PIM-2, and PIM-3) in oncogenesis, the patented PIM kinase inhibitors (2016-Present), and their pharmacological and structural insights have been highlighted. EXPERT OPINION: Recently, PIM kinases viz. PIM-1, PIM-2, and PIM-3 (members of the serine/threonine protein kinase family) as therapeutic targets have attracted considerable interest in oncology especially in hematological malignancies. The patented PIM kinase inhibitors comprised of heterocyclic (fused)ring structure(s) like indole, pyridine, pyrazine, pyrazole, pyridazine, piperazine, thiazole, oxadiazole, quinoline, triazolo-pyridine, pyrazolo-pyridine, imidazo-pyridazine, oxadiazole-thione, pyrazolo-pyrimidine, triazolo-pyridazine, imidazo-pyridazine, pyrazolo-quinazoline and pyrazolo-pyridine etc. showed promising results in cancer chemotherapy.

Recent Advances in the Treatment and Management of Alzheimer's Disease: A Precision Medicine Perspective.

About 60% to 70% of people with dementia have Alzheimer's Disease (AD), a neurodegenerative illness. One reason for this disorder is the misfolding of naturally occurring proteins in the human brain, specifically ß-amyloid (Aß) and tau. Certain diagnostic imaging techniques, such as amyloid PET imaging, tau PET imaging, Magnetic Resonance Imaging (MRI), Computerized Tomography (CT), and others, can detect biomarkers in blood, plasma, and cerebral spinal fluids, like an increased level of ß-amyloid, plaques, and tangles. In order to create new pharmacotherapeutics for Alzheimer's disease, researchers must have a thorough and detailed knowledge of amyloid beta misfolding and other related aspects. Donepezil, rivastigmine, galantamine, and other acetylcholinesterase inhibitors are among the medications now used to treat Alzheimer's disease. Another medication that can temporarily alleviate dementia symptoms is memantine, which blocks the N-methyl-D-aspartate (NMDA) receptor. However, it is not able to halt or reverse the progression of the disease. Medication now on the market can only halt its advancement, not reverse it. Interventions to alleviate behavioral and psychological symptoms, exhibit anti- neuroinflammation and anti-tau effects, induce neurotransmitter alteration and cognitive enhancement, and provide other targets have recently been developed. For some Alzheimer's patients, the FDA-approved monoclonal antibody, aducanumab, is an option; for others, phase 3 clinical studies are underway for drugs, like lecanemab and donanemab, which have demonstrated potential in eliminating amyloid protein. However, additional study is required to identify and address these limitations in order to reduce the likelihood of side effects and maximize the therapeutic efficacy.

Innovative Wound Healing Hydrogel Containing Chicken Feather Keratin and Soy Isoflavone Genistein: In Vivo Studies.

The current study was performed to isolate keratin from chicken feathers with an intention to develop a keratin-genistein wound-healing hydrogel, along with its in vivo analysis. Pre-formulation aspects were analysed by using FTIR; SEM; HPTLC, while gel was characterized for gel strength, viscosity, spreadability, drug content, etc. Additionally, an in vivo study along with biochemical factors against pro-inflammatory factors and histopathological studies were conducted to determine possible wound-healing and anti-inflammatory effects. Pre-formulation studies revealed the presence of amide bonds with region of dense fibrous keratin and an internal porous network in extracted keratin, which corresponds with standard keratin. Evaluation of optimised keratin-genistein hydrogel indicated the development of neutral, non-sticky hydrogel which spread evenly on the skin. In vivo studies in rats indicate higher degrees of wound-healing in combined hydrogel (94.65%) for a duration of 14 days as compared to an individual hydrogel formulation with the development of the epidermis and excessive proliferation of fibrous connective tissue indicating wound repair. Furthermore, the hydrogel inhibited the overexpression of IL-6 gene along with other pro-inflammatory factors, indicating its anti-inflammatory effects. In order to find out the possibility of closure of wounds and anti-inflammatory properties of the novel product, an in vivo investigation into the healing of wounds in laboratory animals was carried out through biochemical (ELISA and qRT-PCR) analyses against inflammatory markers (IL-2, IL-6, IL-1, IL-10, and COX-2) and histopathological (liver, skin, and the kidneys) investigations. Based on the results, we conclude that keratin-genistein hydrogel is a promising therapeutic molecule for the management of wound repair.

3D printing of polylactic acid: recent advances and opportunities.

Bio-based polymers are a class of polymers made by living organisms, a few of them known and commercialized yet. Due to poor mechanical strength and economic constraints, they have not yet seen the extensive application. Instead, they have been an appropriate candidate for biological applications. Growing consumer knowledge of the environmental effect of polymers generated from petrochemical sources and a worldwide transition away from plastics with a lifespan of hundreds of years has resulted in greater interest in such hitherto unattainable sectors. Bio-based polymers come in various forms, including direct or "drop-in" replacements for their petrochemical counterparts with nearly identical properties or completely novel polymers that were previously unavailable, such as polylactide. Few of these bio-based polymers offer significantly improved technical specifications than their alternatives. Polylactic acid (PLA) has been well known in the last decade as a biodegradable thermoplastic source for use in 3DP by the "fused deposition modeling" method. The PLA market is anticipated to accomplish 5.2 billion US dollars in 2020 for its industrial usage. Conversely, 3DP is one of the emerging technologies with immense economic potential in numerous sectors where PLA is one of the critical options as the polymer source due to its environmentally friendly nature, glossiness, multicolor appearance, and ease of printing. The chemical structure, manufacturing techniques, standard features, and current market situation of PLA were examined in this study. This review looks at the process of 3DP that uses PLA filaments in extrusion-based 3DP technologies in particular. Several recent articles describing 3D-printed PLA items have been highlighted.

Recent Updates on Indole Derivatives as Kinase Inhibitors in the Treatment of Cancer.

Cancer is becoming a global threat as its treatment accounts for many challenges. Hence, newer inventions prioritize the requirement of developing novel anticancer agents. In this context, kinases have been exclusively investigated and developed as a promising and novel class of drug targets for anticancer regimen. Indole derivatives have been found to be most effective for targeting multiple kinases, such as PIM, CDK, TK, AKT, SRC, PI3K, PKD, GSK, etc., to inhibit cell proliferation for cancer. Recently, a group of researchers have proposed their research outcomes related to this moiety, such as Zhang et al. described some potent PI3K inhibitors by substitution at the 4th position of the indole ring. Kassis et al. enumerated several potent CDK5 inhibitors by substituting the 2nd and 6th positions of the indole ring. In the present review, we have taken the initiative to summarize structure-activity relationship (SAR) studies of indole derivatives as kinase inhibitors for the development of potential inhibitors.

Recent Advances of PI3 Kinase Inhibitors: Structure Anticancer Activity Relationship Studies.

Phosphatidyl-inositol-3-kinase (PI3K) has emerged as a potential therapeutic target for the development of novel anticancer drugs. The dysregulation of PI3K has been associated with many human malignancies such as breast, colon, endometrial, brain, and prostate cancers. The PI3K kinases in their different isoforms namely α, ß, δ, and γ, encode PIK3CA, PIK3CB, PIK3CD, and PIK3CG genes. Specific gene mutation or overexpression of the protein is responsible for therapeutic failure of current therapeutics. Recently, various PI3K signaling pathway inhibitors have been identified which showed promising therapeutic results by acting on specific isoforms of the kinase too. Several inhibitors containing medicinally privileged scaffolds like oxadiazole, pyrrolotriazine, quinazoline, quinazolinone, quinazoline-chalcone hybrids, quinazoline-sulfonamide, pyrazolochalcone, quinolone hydroxamic acid, benzofuropyridinone, imidazopyridine, benzoxazines, dibenzoxanthene, indoloderivatives, benzimidazole, and benzothiazine derivatives have been developed to target PI3K pathway and/or a specific isoform. The PI3K inhibitors which are under clinical trial studies include GDC-0032, INK1117 for PI3K-α, and AZD8186 for PI3K-ß. This review primarily focuses on the structural insights and structure anticancer activity relationship studies of recent PI3K inhibitors including their clinical stages of development and therapeutic values.

Recent Advances in PI3 Kinase Inhibitors: Anticancer Activities and Structure-Activity Relationships.

Phosphatidyl-inositol-3-kinase (PI3K) has emerged as a potential therapeutic target for the development of novel anticancer drugs. The dysregulation of PI3K has been associated with many human malignancies such as breast, colon, endometrial, brain, and prostate cancers. The PI3K kinases in their different isoforms, namely α, ß, δ, and γ, encode PIK3CA, PIK3CB, PIK3CD, and PIK3CG genes. Specific gene mutation or overexpression of the protein is responsible for the therapeutic failure of current therapeutics. Recently, various PI3K signaling pathway inhibitors have been identified, which showed promising therapeutic results by acting on specific isoforms of the kinase too. Several inhibitors containing medicinally privileged scaffolds like oxadiazole, pyrrolotriazine, quinazoline, quinazolinone, quinazoline-chalcone hybrids, quinazoline-sulfonamide, pyrazolochalcone, quinolone hydroxamic acid, benzofuropyridinone, imidazopyridine, benzoxazines, dibenzoxanthene, indoloderivatives, benzimidazole, and benzothiazine derivatives have been developed to target the PI3K pathway and/or a specific isoform. The PI3K inhibitors under clinical trial studies include GDC-0032, INK1117 for PI3K-α, and AZD8186 for PI3K-ß. This review primarily focuses on the structural insights, anticancer activities, and structure-activity relationship (SARs) studies of recent PI3K inhibitors, including their clinical stages of development and therapeutic values.

PIM kinase inhibitors: Structural and pharmacological perspectives.

The PIM kinase, also known as serine/threonine kinase plays an important role in cancer biology and is found in three different isoforms namely PIM-1, PIM-2, and PIM-3. They are extensively distributed and are implicated in a variety of biological processes, including cell proliferation, cell differentiation, and apoptosis. They act as weak oncogene and whenever expressed in exacerbating forms are responsible for different types of human cancer. Recently, different isoforms of PIM kinase have been identified as a clinical biomarker and potential therapeutic target for personalized treatment of advanced cancer. The inhibition of PIM kinase has become a scientific interest and some inhibitors have been developed and/or are under different phases of clinical trials. Several medicinally privileged heterocyclic ring scaffolds such as pyrrole, pyrimidine, thiazolidine, benzofuran, indole, triazole, oxadiazole, and quinoline derivatives have been synthesized and evaluated for their PIM inhibitory activity. This review comprehensively focuses on pharmacological implications of PIM kinases in oncogenesis, structural insights of PIM inhibitors and their structure-activity relationships (SARs).

Perspectives of medicinally privileged chalcone based metal coordination compounds for biomedical applications.

Recent clinical reports have highlighted the increasing occurrence of drug resistance of known therapeutics. Particularly, antibiotic resistant microorganisms and multidrug resistance have posed a serious threat to health of the people. Since ages, metals and metal complexes have played key role in the development of contemporary chemotherapy. Many organic compounds used in medicine do not have a purely organic mode of action and require traces of metal ions directly or indirectly for activation or biotransformation. For decades, the metallopharmaceuticals have attracted researchers across the globe due to their amplified therapeutic/modulatory effect by altering the pharmacokinetic and pharmacodynamic properties of the complexes towards biological receptors. Medicinally privileged natural and (semi)-synthetic chalcones have already been reported to possess a wide variety of pharmacological effects by modulating diverse molecular targets. The presence of carbonyl, hydroxyl, phenolic oxygen and/or heteroatom(s) in heterocyclic ring system makes them excellent chelating ligand for metal coordination. Particularly, the metal complexes of bidentate chalcone/Schiff base analogs and ferrocenyl chalcones have shown great potential. In this review, the chelating/coordinating property of substituted chalcones, the therapeutic, catalytic, chemosensing and photosensitizing potential of various metal-chalcone complexes, their structural features and structure activity relationships (SARs) have been highlighted. Further, the understanding of coordination mode, their stoichiometric characteristics, and mode of action(s), this review may be helpful for medicinal and bioinorganic chemists to design and develop novel, more potent, safe, selective and cost-effective chalcone-based coordination compounds for diverse biomedical applications.

Chalcone Derivatives: Anti-inflammatory Potential and Molecular Targets Perspectives.

Chalcone or (E)-1,3-diphenyl-2-propene-1-one scaffold has gained considerable scientific interest in medicinal chemistry owing to its simple chemistry, ease in synthesizing a variety of derivatives and exhibiting a broad range of promising pharmacological activities by modulating several molecular targets. A number of natural and (semi-) synthetic chalcone derivatives have demonstrated admirable anti-inflammatory activity due to their inhibitory potential against various therapeutic targets like Cyclooxygenase (COX), Lipooxygenase (LOX), Interleukins (IL), Prostaglandins (PGs), Nitric Oxide Synthase (NOS), Leukotriene D4 (LTD4), Nuclear Factor-κB (NF- κB), Intracellular Cell Adhesion Molecule-1 (ICAM-1), Vascular Cell Adhesion Molecule-1 (VCAM-1), Monocyte Chemoattractant Protein-1 (MCP-1) and TLR4/MD-2, etc. The chalcone scaffold with hydroxyl, methoxyl, carboxyl, prenyl group and/or heterocyclic ring substitution like thiophene/furan/indole showed promising anti-inflammatory activity. In this review, a comprehensive study (from the year 1991 to 2016) on multi-targets of inflammatory interest, related inflammation reactions and their treatment by chalcone-based inhibitors acting on various molecular targets entailed in inflammation, Structure-Activity Relationships (SARs), Mechanism of Actions (MOAs), and patents are highlighted.

MEK inhibitors in oncology: a patent review (2015-Present).

INTRODUCTION: The RAS/RAF/MEK/ERK and PI3K/AKT/mTOR signaling pathways have been identified as promising therapeutic targets for cancer therapy. Over-activation of these pathways and their components including gene mutations has been considered as one of the major causes of melanoma. Mitogen-activated protein kinase (MEK) is a downstream kinase of RAS pathway found in two different forms MEK1/2. The MEK inhibitors in combination with other kinase/mutant gene inhibitors have shown promising results in patients with metastatic melanoma. Areas covered: A comprehensive review of the patent literature (2015 - Present) on MEK inhibitors, their combinations with other kinase inhibitors and structural insights has been highlighted. Expert opinion: Recently mitogen-activated protein kinase (MEK) inhibitors have attracted considerable interest in oncology especially in melanoma. The MEK inhibitors showed promising results in patients with metastatic melanoma harboring mutant genes such as BRAF, KRAS. The MEK1/2 inhibitors in combination with BRAF, KRAS and/or PI3K inhibitors showed promising results in mutated colorectal, pancreatic adenocarcinoma, solid tumor, and relapsed/refractory melanoma. The combination delays the onset of acquired resistance, resulting in increased progression-free and overall survival. The combination and/or multi-targeted kinase/mutant gene inhibitors may be a therapeutic option for the personalized cancer treatment of patients with relapsed or refractory multiple myeloma.

K-Ras and its inhibitors towards personalized cancer treatment: Pharmacological and structural perspectives.

The discovery of genetic, genomic and clinical biomarkers have revolutionized the treatment option in the form of personalized medicine which allows to accurately predict a person's susceptibility/progression of disease, the patient's response to therapy, and maximize the therapeutic outcome in terms of low/no toxicity for a particular patient. Recently, the U.S. Food and Drug Administration has realized the contribution of pharmacogenomics in better healthcare and advocated the consideration of pharmacogenomic principles in making safer and more effective drug. Many anticancer drugs show reduced or no response in cancer patients with tumor specific gene mutations such as B-Raf and K-Ras. The high incidence of K-Ras mutation has been reported in pancreatic, colon, and lung carcinomas. The identification of K-Ras as a clinical biomarker and potential therapeutic target has attracted the scientific community to develop effective and precise anticancer drug. Inhibitors which block farnesylation of Ras have been developed or under clinical trial studies. Tipifarnib, approved by USFDA for the treatment of elderly acute leukemia is a Ras pathway inhibitor. Some peptidomimetics and bi-substrate inhibitors like FTI 276, FTI 277, B956, B1086, L731, L735, L739, L750, BMS-214662, L778123, and L778123 are under clinical trials. Recently mutant K-Ras has been considered as potential biomarker and target for precise cancer therapy. This review focuses primarily on the Ras/Raf/MEK/ERK signaling pathway including K-Ras mutation as therapeutic target, inhibitors and their structure activity relationships (SARs) for the design and development of anticancer agents.

Triggering PIK3CA Mutations in PI3K/Akt/mTOR Axis: Exploration of Newer Inhibitors and Rational Preventive Strategies.

BACKGROUND: PIK3CA gene was found in generation of p110 alpha (p110α) protein through an instruction process. p110 alpha acts as a catalytic subunit of phosphatidylinositol 3-kinase (PI3K) proceed phosphorylation of signal molecules through PI3K pathway. This PI3K involved in regulation of cellular growth, transformation, adhesion, apoptosis, survival and motility. In some situations the PI3K/Akt pathway get altered due to mutation in PIK3CA gene produced oncogenic event in human malignancy. METHODS: The goal of this work is to describe the PI3K signaling pathway including mutational activation of PIK3CA gene and inhibitors have been developed or under clinical trials for the targeting of PI3K or PI3KR kinases. RESULTS: Various inhibitors such as Morpholine, pyrimidines, benzenesulfonamide, pyridopyrimidinone, imidazo[1,5]naphthyridine, benzeneacylhydrazones, thienopyrimidine, aminopyridopyrimidine, imidazopyridine, imidazo[1,2-a]pyridine, thiazolopyrimidinone, quinolines and quinoxalines, thieno[3,2-b]pyran-7-one, morpholino-1,3-benzoxazines, quinalozinones, pyrido [3,2-d]pyrimidines, benzo[d]thiazol-2-yl)acetamide, aminopyrimidines, chalcone , azaindole, pyrazolopyrimidine and pyridine, thienobenzoxepin, phenylquinazolines , pyrazolo[1,5-a]pyridines , imidazolo-pyrimidine etc. were investigated under laboratory level as PI3K inhibitors in which few having PI3K and mTOR dual inhibitory activities. CONCLUSION: After a long term of prognostic standpoint, PIK3CA mutations discussed as a major target for various cancers. These PIK3CA mutations were found in various exon including 1,2,4,6,7,9,13,18 and 20 which may be a cause of different cancers such as breast, colon, ovarian, gastric, brain, lung etc. In clinical trials these mutations still remain question marks for presence or absence to the scientist regarding future perspective. The opinion of these studies is to development of more specific inhibitors of PI3K pathway which produce tremendous impact on various cancers developed due to PIK3CA mutations.

Therapeutic potential of chalcones as cardiovascular agents.

Cardiovascular diseases are the leading cause of death affecting 17.3 million people across the globe and are estimated to affect 23.3 million people by year 2030. In recent years, about 7.3 million people died due to coronary heart disease, 9.4 million deaths due to high blood pressure and 6.2 million due to stroke, where obesity and atherosclerotic progression remain the chief pathological factors. The search for newer and better cardiovascular agents is the foremost need to manage cardiac patient population across the world. Several natural and (semi) synthetic chalcones deserve the credit of being potential candidates to inhibit various cardiovascular, hematological and anti-obesity targets like angiotensin converting enzyme (ACE), cholesteryl ester transfer protein (CETP), diacylglycerol acyltransferase (DGAT), acyl-coenzyme A: cholesterol acyltransferase (ACAT), pancreatic lipase (PL), lipoprotein lipase (LPL), calcium (Ca(2+))/potassium (K(+)) channel, COX-1, TXA2 and TXB2. In this review, a comprehensive study of chalcones, their therapeutic targets, structure activity relationships (SARs), mechanisms of actions (MOAs) have been discussed. Chemically diverse chalcone scaffolds, their derivatives including structural manipulation of both aryl rings, replacement with heteroaryl scaffold(s) and hybridization through conjugation with other pharmacologically active scaffold have been highlighted. Chalcones which showed promising activity and have a well-defined MOAs, SARs must be considered as prototype for the design and development of potential anti-hypertensive, anti-anginal, anti-arrhythmic and cardioprotective agents. With the knowledge of these molecular targets, structural insights and SARs, this review may be helpful for (medicinal) chemists to design more potent, safe, selective and cost effective chalcone derivatives as potential cardiovascular agents.

PI3K/Akt/mTOR and Ras/Raf/MEK/ERK signaling pathways inhibitors as anticancer agents: Structural and pharmacological perspectives.

The protein kinases regulate cellular functions such as transcription, translation, proliferation, growth and survival by the process of phosphorylation. Over activation of signaling pathways play a major role in oncogenesis. The PI3K signaling pathway is dysregulated almost in all cancers due to the amplification, genetic mutation of PI3K gene and the components of the PI3K pathway themselves. Stimulation of the PI3K/Akt/mTOR and Ras/Raf/MEK/ERK pathways enhances growth, survival, and metabolism of cancer cells. Recently, the PI3K/Akt/mTOR and Ras/Raf/MEK/ERK signaling pathways have been identified as promising therapeutic targets for cancer therapy. The kinase inhibitors with enhanced specificity and improved pharmacokinetics have been considered for design and development of anticancer agents. This review focuses primarily on the Ras/Raf/MEK/ERK and PI3K/Akt/mTOR signaling pathways as therapeutic targets of anticancer drugs, their specific and dual inhibitors, structure activity relationships (SARs) and inhibitors under clinical trials.

Chalcone scaffolds as anti-infective agents: structural and molecular target perspectives.

In recent years, widespread outbreak of numerous infectious diseases across the globe has created havoc among the population. Particularly, the inhabitants of tropical and sub-tropical regions are mainly affected by these pathogens. Several natural and (semi) synthetic chalcones deserve the credit of being potential anti-infective candidates that inhibit various parasitic, malarial, bacterial, viral, and fungal targets like cruzain-1/2, trypanopain-Tb, trans-sialidase, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), fumarate reductase, falcipain-1/2, ß-hematin, topoisomerase-II, plasmepsin-II, lactate dehydrogenase, protein kinases (Pfmrk and PfPK5), and sorbitol-induced hemolysis, DEN-1 NS3, H1N1, HIV (Integrase/Protease), protein tyrosine phosphatase A/B (Ptp-A/B), FtsZ, FAS-II, lactate/isocitrate dehydrogenase, NorA efflux pump, DNA gyrase, fatty acid synthase, chitin synthase, and ß-(1,3)-glucan synthase. In this review, a comprehensive study (from Jan. 1982 to May 2015) of the structural features of anti-infective chalcones, their mechanism of actions (MOAs) and structure activity relationships (SARs) have been highlighted. With the knowledge of molecular targets, structural insights and SARs, this review may be helpful for (medicinal) chemists to design more potent, safe, selective and cost effective anti-infective agents.

Anti-cancer chalcones: Structural and molecular target perspectives.

Chalcone or (E)-1,3-diphenyl-2-propene-1-one scaffold remained a fascination among researchers in the 21st century due to its simple chemistry, ease of synthesis and a wide variety of promising biological activities. Several natural and (semi) synthetic chalcones have shown anti-cancer activity due to their inhibitory potential against various targets namely ABCG2/P-gp/BCRP, 5α-reductase, aromatase, 17-ß-hydroxysteroid dehydrogenase, HDAC/Situin-1, proteasome, VEGF, VEGFR-2 kinase, MMP-2/9, JAK/STAT signaling pathways, CDC25B, tubulin, cathepsin-K, topoisomerase-II, Wnt, NF-κB, B-Raf and mTOR etc. In this review, a comprehensive study on molecular targets/pathways involved in carcinogenesis, mechanism of actions (MOAs), structure activity relationships (SARs) and patents granted have been highlighted. With the knowledge of molecular targets, structural insights and SARs, this review may be helpful for (medicinal) chemists to design more potent, safe, selective and cost effective anti-cancer chalcones.

Chalcones and their therapeutic targets for the management of diabetes: structural and pharmacological perspectives.

Diabetes Mellitus (DM) is the fastest growing metabolic disorder affecting about 387 million people across the globe and is estimated to affect 592 million people by year 2030. The search for newer anti-diabetic agents is the foremost need to control the accelerating diabetic population. Several natural and (semi) synthetic chalcones deserve the credit of being potential candidates that act by modulating the therapeutic targets PPAR-γ, DPP-4, α-glucosidase, PTP1B, aldose reductase, and stimulate insulin secretion and tissue sensitivity. In this review, a comprehensive study (from January 1977 to October 2014) of anti-diabetic chalcones, their molecular targets, structure activity relationships (SARs), mechanism of actions (MOAs) and patents have been described. The compounds which showed promising activity and have a well-defined MOAs, SARs must be considered as prototype for the design and development of potential anti-diabetic agents. They should be evaluated critically at all clinical stages to ensure their therapeutic and toxicological profile to meet the demand of diabetics.