Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 23, Issue 6, 2023

Cancer is a type of human cell degenerative disease that has afflicted a large number of people for years. Cancer is caused due to the abnormal proliferation of cells in any part of the body. Most of the prescribed anticancer drugs are synthetic in nature and have been reported with enormous adverse effects. The researchers are very much enthusiastic about the use of natural compounds and their derivatives, which have been reported with less toxicity. Natural compounds have emerged as promising synergistic compounds with potential anticancer effects. In vitro anticancer activity of natural compounds with special reference to camphor and menthol has been investigated against different cancer cell lines. It has been found that camphor and menthol derivatives have potential cytotoxic activity. The present literature review outlines the various methods for the synthesis of camphor and menthol derivatives, which have potential cytotoxic activity. It highlights various cancer cell lines, which are the target of these camphor and menthol derivatives as ligands, along with structure-activity studies.

Cancer is known as a notorious disease responsible for threatening millions of lives every year. Natural products which act by disrupting the microtubule assembly and dynamics have proven to be highly successful as anticancer agents but their high toxicity owing to lower selectivity has limited their usage. Recently, Noscapine (NOS), a known anti-tussive, has come out to be an effective anti-tubulin candidate with far lesser toxicity. Since its first report as an anti-mitotic agent in 1998, NOS has been extensively studied and modified by various groups of researchers to optimize its anti-tubulin activity. In this review, the recent advancements about the potential of these therapeutic candidates against various cancers have been compiled and analyzed for their inhibitory mechanism in distinct health conditions. It has been observed that the non-polar substitutions (e.g., halides, aryl groups) at specific sites (9-position and N-sites of isoquinoline ring; and modification of a methoxy group) have an enhanced effect on efficacy. The mechanistic studies of NOS and its modified analogs have shown their inhibitory action primarily through interaction with microtubules dynamics thus disrupting the cell-cycle and leading to apoptosis. This review highlights the latest research in the field by providing a rich resource for the researchers to have a hands-on analysis of NOS analogs and the inhibitory action in comparison to other microtubule disrupting anti-cancer agents. The article also documents the newer investigations in studying the potential of noscapine analogs as possible anti-microbial and antiviral agents.

Antibody-Drug Conjugates (ADCs) are basically a targeted drug delivery system where tumour antigenspecific antibodies are used for targeting particular tumor cells and cytotoxic materials are conjugated with it by a linker molecule. Till now, twelve ADCs have been approved by FDA for clinical use. Majority of the approved ADCs are against hematological cancer. Here in this review, we will discuss the combinations of targeted ligands (antigen) specific antibodies, different types of cytotoxic drugs (payload/warheads) and linker moieties which are being used for the development of successful FDA approved ADCs. We will discuss new ADC formulations which completed clinical trials or underwent advance phases of clinical trials against different types of solid tumours. New ADC formulation or recently developed its prototypes against solid tumour models in preclinical studies will be discussed precisely in this review article.

Breast Cancer is one of the most notorious cancer affecting women globally. Current therapies available for breast cancer treatment have certain limited efficacy; develop drug resistance and severe adverse effects. Thus, identifying novel therapies for treatment will reduce the devastating effect on cancer survivors. The exhilarating and fastgrowing studies on flavonoids have evidenced that it has the potential to inflect various antitumor activity and modulate various signal transduction pathways in carcinogenesis. Flavonoids also have been found to regulate cellular metabolism and oxidative stress, cell cycle progression, angiogenesis and metastasis, ultimately preventing the progression of the diseases. As per the reports, a flavonoid-rich diet appears to be the most potent and promising approach to abate the risk of cancer. Thus, now a day, these are the prime target for drug discovery research. Based on existing findings, it can be concluded that beyond the currently employed chemotherapeutics, natural products (like flavonoids) exhibit pleiotropic, multi-target activities and are budding as possible complementary chemopreventive molecules against breast cancer with fewer side effects than conventional therapy. In this review, we comprehensively highlight an outline of the multiple pleiotropic pharmacological effects of various major classes of flavonoids on breast cancer with their specific mechanisms underlying its anticancer effect.

Objective: This article aims to establish a liquid biopsy system for gene detection of circulating tumor cells (CTC) in lung cancer, systematically analyze the significance of osimertinib resistance, and formulate an individualized diagnosis and treatment plan. Methods: Liposome-contained magnetic microspheres coated with Fe3O4 nanoparticles were synthesized by microemulsion, and the surface was modified with EGFR antibody to form EGFR/EpCAM multi-site liposome-contained immunomagnetic microspheres (IMMSs). The CTCs were isolated and identified from peripheral blood samples and the cell lines of lung cancer patients collected by the multi-site liposome-contained IMMSs. To investigate the effects of the order of use of IMMSs sequence at different sites on the sorting and trapping efficiency of non-small-cell lung cancer (NSCLC) cells . The preliminary verification of drug-resistant gene function and dynamic monitoring of CTCs in 20 patients with EGFR-positive NSCLC were screened and statistically analyzed before and after osimertinib treatment. Sensitivity analysis and drug resistance evaluation of oxitidine were detected in vitro. Results: Results showed the prepared multi-site liposome-contained IMMSs had high stability and specificity. The number of CTCs in blood samples of the patients with NSCLC was detected, revealing high sorting efficiency, and positive sorting rate reaching more than 90%. We investigated the effect of osimertinib on the HER-2 expression on the EGFR-mutated NSCLC cells and found that osimertinib increased the expression of HER-2 on the cell surface of NSCLC cell lines., And further explored the therapeutic potential of osimertinib combined with T-DM1 at different dosing times. Conclusion: Our results demonstrate that the prepared multi-site liposome-contained IMMSs can efficiently isolate CTCs from the peripheral blood in lung cancer. Combined with the experimental data about osimertinib can be effectively identified, the resistant genes of NSCLC including EGFR, which will provide a new scientific basis for guiding clinical medication and formulating individualized treatment plans.

Background: Conventional chemotherapeutic treatment of colorectal cancer has low efficiency because of its high toxicity. Several studies identified natural compounds as potential antitumor agents by inducing cancer cell cycle arrest or apoptosis and exhibiting a potential synergy in drug combination therapy. Natural compounds derived from plants represent an important source of pharmacologic agents toward several diseases. For example, the Tunisian Thymelaeaceae plants are used in folk medicine for the treatment of different pathologies such as diabetes and hypertension. Objective: The Thymelaea hirsuta L. extracts were evaluated for their anti-tumoral activities and their adjuvant potential that could be used in conventional colorectal cancer therapy. Methods: Fractionation of total methanolic extract from the plant leaves provided 4 fractions using vacuum liquid chromatography. The cytotoxic activities of these fractions were tested toward colorectal cancer cells. Results: Ethyl acetate fraction (E2 fraction) induced cell cycle arrest and apoptosis by activating caspase-3. E2 fraction inhibited cell invasion by reducing integrin α5 expression and FAK phosphorylation. Moreover, E2 fraction potentialized colorectal cancer cells to 5-FU treatment. Conclusion: The selected plant Thymelaea hirsuta is the source of natural compounds that inhibited cell growth and invasion and induced cell cycle arrest in colorectal cancer cells. The most interesting result was their potential synergy in 5-FU combination treatment. Further analysis will identify the active compounds and confirm their role in chemotherapeutic treatment by sensitizing colorectal cancer cell to anti-cancer drugs.

Background: Galbanic acid (GBA) is a sesquiterpene coumarin with valuable pharmacological effects. Adult T-cell lymphoma (ATL) is an aggressive lymphoid malignancy with a low survival rate. Although arsenic trioxide (ATO) is a standard therapeutic agent for ATL treatment, the efficacy of chemotherapy is limited due to the chemoresistance of cells. Objective: The present study was carried out to investigate whether GBA in combination with ATO would improve cytotoxicity against ATL cells. Methods: GBA was isolated from the roots of Ferula szowitsiana by column chromatography on silica gel. MT-2 cells were treated with 20 μM GBA + 4 μM ATO, and viability was evaluated by alamarBlue assay. The cell cycle was analyzed by PI staining, while the activity of P-glycoprotein (P-gp) was evaluated by mitoxantrone efflux assay. To understand the molecular mechanisms of GBA effects, the expression of NF-ΚB (RelA), P53, CDK4, c-MYC, c-FLIPL, and c-FLIPS was evaluated using real-time PCR. Results: Combinatorial use of GBA + ATO significantly reduced the viability of MT-2 cells and induced cell cycle arrest in the sub-G1 phase. GBA improved mitoxantrone accumulation in cells, indicating that this agent has inhibitory effects on the functionality of the P-gp efflux pump. Moreover, real-time PCR analysis revealed that GBA + ATO negatively regulated the expression of P53, CDK4, c-FLIPL, and c-FLIPS. Conclusion: Due to the interesting effects of GBA on the accumulation and toxicity of ATO, combinatorial use of these agents could be considered a new therapeutic approach for ATL treatment.

Background: The blockade of programmed cell death-1 (PD-1) and recombinant human endostatin can be used for the treatment of non-small cell lung cancer (NSCLC) and its metastasis. This study aims to explore the therapeutically potential of PD-1 blockade plus Endostar in brain metastasis of NSCLC. Methods: The mouse brain metastases model was established using Lewis lung carcinoma luciferase (LLC-Luc) and PC-9-Luc cells. Tumor metastasis in the brain and tumor burden were analyzed by using bioluminescence imaging (BLI), qRT-PCR and ELISA which were used to determine the mRNA and protein levels of biomarkers in tumor tissues. Immunohistochemical staining was used to determine the expression and location of CD31 in tumor tissues in the brain. Results: Treatment with anti-PD-1 and Endostar suppressed tumor metastasis in the brain and prolonged overall survival rate in LLC-Luc and PC-9-Luc brain metastases mouse model. In addition, treatment with anti-PD-1 and Endostar inhibited the expressions of CD31 and VEGF in tumor tissues in the brain. Furthermore, treatment with anti-PD- 1 and Endostar significantly suppressed the levels of IL1β, IFNγ, and TGFβ in the tumor tissues. Conclusion: The combination of PD-1 blockade and endostar suppressed brain metastases of NSCLC.

Background: Lung cancer is the leading cause of cancer-associated death and the first most diagnosed cancer in the world. More than 2 million new cases are diagnosed and 1.6 million people die due to lung cancer every year. It is urgent to explore novel drugs and approaches for lung cancer treatment. Cinobufotalin is a TCM isolated from dried toad venom, which has been used to treat lung cancer. However, the precise mechanism remains unclear. Objective: This study was to investigate the mechanism of cinobufotalin treated in lung cancer. Methods: Cell growth was identified by Cell Counting Kit-8 (CCK-8) assay. Besides, ferroptosis of lung cancer cells was determined by intracellular iron content, lactate dehydrogenase (LDH) release and mitochondrial membrane potential. Moreover, RNA levels and proteins were detected by quantitative reverse transcription-PCR (qRT-PCR) and Western blot (WB), respectively. In addition, the regulatory effect of hsa-miR-367-3p on TFRC was confirmed by luciferase reporter assay. Results: This study indicated that cinobufotalin suppressed lung cancer cell growth through resibufogenin. Besides, cinobufotalin induced ferroptosis in lung cancer cells through resibufogenin. Moreover, cinobufotalin increased lncRNA LINC00597 level, whereas it downregulated hsa-miR-367-3p expression in lung cancer cells via resibufogenin. In addition, ferroptosis inducer transferrin receptor (TFRC) was the target of hsa-miR-367-3p, and lncRNA LINC00597 upregulates TFRC expression through sponging hsa-miR-367-3p in lung cancer cells. Conclusion: In summary, this study indicated that cinobufotalin induced ferroptosis to suppress lung cancer cell growth by lncRNA LINC00597/hsa-miR-367-3p/TFRC pathway via resibufogenin might provide novel therapeutic targets for lung cancer therapy.

Background: 1, 8-naphthimide is a novel tumor inhibitor targeting nuclear DNA, which can be used to design and develop anti-osteosarcoma drugs. Objective: Quantitative structure-activity relationship (QSAR) model was established to predict the physical properties of compounds. Methods: In this study, gene expression programming (GEP) was used to build a nonlinear quantitative structureactivity relationship (QSAR) model with descriptors and to predict the activity of a serials novel DNA-targeted chemotherapeutic agents. These descriptors were calculated in CODESSA software and selected from the descriptor pool based on heuristics. Three descriptors were selected to establish a multiple linear regression model. The best nonlinear QSAR model with a correlation coefficient of 0.89 and 0.82 and mean error of 0.02 and 0.06 for the training and test sets were obtained. Results: The results showed that the model established by GEP had better stability and predictive ability. The small molecular docking experiment of 32 compounds was carried out in SYBYL software, and it was found that compound 7A had reliable molecular docking ability. Conclusion: The established model reveals the factors affecting the activity of DNA inhibitors and provides direction and guidance for the further design of highly effective DNA-targeting drugs for osteosarcoma.