Editorial for the Special Issue "Advances in the Development of Anticancer Drugs".

As mortality rates for other leading causes of death, such as stroke and coronary heart disease, decline in many parts of the world, cancer is becoming the leading cause of death worldwide, with the number of yearly new cases expected to rise to about 30 million by 2040 [...].

Multifaceted approach toward mapping out the anticancer properties of small molecules via in vitro evaluation on melanoma and nonmelanoma skin cancer cells, and in silico target fishing.

Melanoma and nonmelanoma skin cancers are among the most prevalent and most lethal forms of skin cancers. To identify new lead compounds with potential anticancer properties for further optimization, in vitro assays combined with in-silico target fishing and docking have been used to identify and further map out the antiproliferative and potential mode of action of molecules from a small library of compounds previously prepared in our laboratory. From screening these compounds in vitro against A375, SK-MEL-28, A431, and SCC-12 skin cancer cell lines, 35 displayed antiproliferative activities at the micromolar level, with the majority being primarily potent against the A431 and SCC-12 squamous carcinoma cell lines. The most active compounds 11 (A431: IC50 = 5.0 µM, SCC-12: IC50 = 2.9 µM, SKMEL-28: IC50 = 4.9 µM, A375: IC50 = 6.7 µM) and 13 (A431: IC50 = 5.0 µM, SCC-12: IC50 = 3.3 µM, SKMEL-28: IC50 = 13.8 µM, A375: IC50 = 17.1 µM), significantly and dose-dependently induced apoptosis of SCC-12 and SK-MEL-28 cells, as evidenced by the suppression of Bcl-2 and upregulation of Bax, cleaved caspase-3, caspase-9, and PARP protein expression levels. Both agents significantly reduced scratch wound healing, colony formation, and expression levels of deregulated cancer molecular targets including RSK/Akt/ERK1/2 and S6K1. In silico target prediction and docking studies using the SwissTargetPrediction web-based tool suggested that CDK8, CLK4, nuclear receptor ROR, tyrosine protein-kinase Fyn/LCK, ROCK1/2, and PARP, all of which are dysregulated in skin cancers, might be prospective targets for the two most active compounds. Further validation of these targets by western blot analyses, revealed that ROCK/Fyn and its associated Hedgehog (Hh) pathways were downregulated or modulated by the two lead compounds. In aggregate, these results provide a strong framework for further validation of the observed activities and the development of a more comprehensive structure-activity relationship through the preparation and biological evaluation of analogs.

The Fundamental Role of Oxime and Oxime Ether Moieties in Improving the Physicochemical and Anticancer Properties of Structurally Diverse Scaffolds.

The present review explores the critical role of oxime and oxime ether moieties in enhancing the physicochemical and anticancer properties of structurally diverse molecular frameworks. Specific examples are carefully selected to illustrate the distinct contributions of these functional groups to general strategies for molecular design, modulation of biological activities, computational modeling, and structure-activity relationship studies. An extensive literature search was conducted across three databases, including PubMed, Google Scholar, and Scifinder, enabling us to create one of the most comprehensive overviews of how oximes and oxime ethers impact antitumor activities within a wide range of structural frameworks. This search focused on various combinations of keywords or their synonyms, related to the anticancer activity of oximes and oxime ethers, structure-activity relationships, mechanism of action, as well as molecular dynamics and docking studies. Each article was evaluated based on its scientific merit and the depth of the study, resulting in 268 cited references and more than 336 illustrative chemical structures carefully selected to support this analysis. As many previous reviews focus on one subclass of this extensive family of compounds, this report represents one of the rare and fully comprehensive assessments of the anticancer potential of this group of molecules across diverse molecular scaffolds.

Silicon switch: Carbon-silicon Bioisosteric replacement as a strategy to modulate the selectivity, physicochemical, and drug-like properties in anticancer pharmacophores.

Bioisosterism is one of the leading strategies in medicinal chemistry for the design and modification of drugs, consisting in replacing an atom or a substituent with a different atom or a group with similar chemical properties and an inherent biocompatibility. The objective of such an exercise is to produce a diversity of molecules with similar behavior while enhancing the desire biological and pharmacological properties, without inducing significant changes to the chemical framework. In drug discovery and development, the optimization of the absorption, distribution, metabolism, elimination, and toxicity (ADMETox) profile is of paramount importance. Silicon appears to be the right choice as a carbon isostere because they possess very similar intrinsic properties. However, the replacement of a carbon by a silicon atom in pharmaceuticals has proven to result in improved efficacy and selectivity, while enhancing physicochemical properties and bioavailability. The current review discusses how silicon has been strategically introduced to modulate drug-like properties of anticancer agents, from a molecular design strategy, biological activity, computational modeling, and structure-activity relationships perspectives.

Identification of new fisetin analogs as kinase inhibitors: Data on synthesis and anti-skin cancer activities evaluation.

This article contains supplemental datasets of the recently published related research article "Synthesis, Inverse Docking-Assisted Identification and in vitro Biological Characterization of Flavonol-based Analogs of Fisetin as c-Kit, CDK2 and mTOR Inhibitors against Melanoma and Non-melanoma Skin Cancers" by Roy et al., [1]. It provides in-depth data not included in the original co-submission on the biophysical, molecular docking, and biological characterization of newly synthesized flavonol-based analogs of fisetin, a natural dietary small molecule with anticancer and anti-inflammatory properties. These synthetic small molecules were investigated as new, potential single and/or multi-kinase inhibitors of the cyclin-dependent kinase-2 (CDK2), receptor tyrosine kinases (c-KITs), and mammalian targets of rapamycin (mTOR) targets, potentially active against melanoma or non-melanoma skin cancers. Furthermore, this data-in-brief article comprises additional sets of results on several aspects of the properties of the dual and multiple kinase inhibitor compounds' effects that were not presented in the associated article, including the activated targets that are dysregulated in skin cancers; the effects on markers of apoptosis; on colony formation; and in scratch wound healing assays. The study has identified a panel of novel fisetin analogs that are either single- or multi-kinase inhibitors, which may be further developed as active for the treatment of melanoma and non-melanoma skin cancers. The dataset presented herein will be utilized for additional studies aiming to establish a biological platform to steer for predictive and experimental screening of novel flavonoids and analogs in relevant organoids, humanized animal models and in vivo disease models. The present results should also serve as a key stepping-stone towards enabling target-structure-based design, synthesis and initial testing of novel analogs or derivatives of fisetin. The current study may eventually lead to the development of safe, promising and preclinical candidate entities for treatment of skin and other forms of cancers as well as various other human diseases, which can possibly add to the general armamentarium of promising and safe drugs for health promotion.

Synthesis, inverse docking-assisted identification and in vitro biological characterization of Flavonol-based analogs of fisetin as c-Kit, CDK2 and mTOR inhibitors against melanoma and non-melanoma skin cancers.

Due to hurdles, including resistance, adverse effects, and poor bioavailability, among others linked with existing therapies, there is an urgent unmet need to devise new, safe, and more effective treatment modalities for skin cancers. Herein, a series of flavonol-based derivatives of fisetin, a plant-based flavonoid identified as an anti-tumorigenic agent targeting the mammalian targets of rapamycin (mTOR)-regulated pathways, were synthesized and fully characterized. New potential inhibitors of receptor tyrosine kinases (c-KITs), cyclin-dependent kinase-2 (CDK2), and mTOR, representing attractive therapeutic targets for melanoma and non-melanoma skin cancers (NMSCs) treatment, were identified using inverse-docking, in vitro kinase activity and various cell-based anticancer screening assays. Eleven compounds exhibited significant inhibitory activities greater than the parent molecule against four human skin cancer cell lines, including melanoma (A375 and SK-Mel-28) and NMSCs (A431 and UWBCC1), with IC50 values ranging from 0.12 to < 15 µM. Seven compounds were identified as potentially potent single, dual or multi-kinase c-KITs, CDK2, and mTOR kinase inhibitors after inverse-docking and screening against twelve known cancer targets, followed by kinase activity profiling. Moreover, the potent compound F20, and the multi-kinase F9 and F17 targeted compounds, markedly decreased scratch wound closure, colony formation, and heightened expression levels of key cancer-promoting pathway molecular targets c-Kit, CDK2, and mTOR. In addition, these compounds downregulated Bcl-2 levels and upregulated Bax and cleaved caspase-3/7/8 and PARP levels, thus inducing apoptosis of A375 and A431 cells in a dose-dependent manner. Overall, compounds F20, F9 and F17, were identified as promising c-Kit, CDK2 and mTOR inhibitors, worthy of further investigation as therapeutics, or as adjuvants to standard therapies for the control of melanoma and NMSCs.

Inosine 5'-Monophosphate Dehydrogenase (IMPDH) as a Potential Target for the Development of a New Generation of Antiprotozoan Agents.

Inosine-5'-monophosphate dehydrogenase (IMPDH) is a metabolic enzyme that catalyzes the critical step in guanine nucleotide biosynthesis, and thus is at the center of cell growth and proliferation. However, although this enzyme has been exploited as potential target for the development of immunosuppressive, anticancer, and antiviral agents, the functional importance of IMPDH as a promising antiprotozoan drug target is still in its infancy mainly because of the availability of alternative nucleotides metabolic pathways in many of these parasites. This situation suggests that the inhibition of IMPDH might have little to no effect on the survival of protozoan parasites. As a result, no IMPDH inhibitor is currently commercially available or has advanced to clinical trials as a potential antiprotozoan drug. Nevertheless, recent advances toward the development of selective inhibitors of the IMPDH enzyme from Crystosporidium parvum as potential drug candidates against cryptosporidiosis should revive further investigations of this drug target in other protozoa parasites. The current review examines the chemical structures and biological activities of reported protozoan's IMPDH inhibitors. SciFinder was used to broadly pinpoint reports published on the topic in the chemical literature, with no specific time frame. Opportunities and challenges towards the development of inhibitors of IMPDH enzymes from protozoa parasites as potential chemotherapies toward the respective diseases they cause are also discussed.

Inhibitors of tubulin assembly identified through screening a compound library.

Tubulin is the proposed target for drugs against cancer and helminths and is also a validated target in kinetoplastid parasites. With the aim of identifying new lead compounds against Leishmania sp., tubulin isolated from L. tarentolae was used to screen a 10 000 compound library. One compound, Chembridge No. 7992831 (5), displayed an IC(50) of 13 microm against Leishmania tubulin in an in vitro assembly assay and showed a greater than threefold selectivity over mammalian tubulin. Another compound, Chembridge No. 9067250 (8), exhibited good activity against mammalian tubulin (IC(50) = 5.0 microm). This compound was also toxic to several cancer cell lines with IC(50) values in the region of 1 microm. Subsequent testing of analogues of 8 contained within the library identified two compounds with greater potency against mammalian tubulin (IC(50) values of 1.1 and 2.8 microm). The more potent antitubulin agent also showed promising activity against cancer cell lines in vitro, with IC(50) values ranging from 0.18 to 0.73 microm.

Depsipeptides from microorganisms: a new class of antimalarials.

Depsipeptides are a large group of natural products produced by fungi, actinomycetes, cyanobacteria, higher plants and marine organisms. This family of compounds is known to exhibit a wide range of biological activities, and thanks to the progress of isolation techniques and the advances of methods for structure determination, the numbers of depsipeptides having both unique structures and attractive biological activities are increasing. Many of these compounds have shown a wide range of biological activities, and some are in clinical use or have entered human clinical trials as antibiotic or anticancer agents. However, only a handful of them have been evaluated for their antimalarial activity. This paper aims to review the recent advances in depsipeptides as potential antimalarial compounds.