Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 23, Issue 12, 2023

Neuroprotection is one of the hot topics in medicine. Alzheimer’s disease, amyotrophic lateral sclerosis, retinal pigment epithelial (RPE) degeneration, and axonal degeneration have been studied for the involvement of NAD depletion. Localized NAD⁺ depletion could lead to overactivation and crowding of local NAD⁺ salvage pathways. It has been stated that NAD⁺ depletion caused by PARPs and PAR cycling has been related to metabolic diseases and cancer. Additionally, it is now acknowledged that SARM1 dependent NAD⁺ depletion causes axon degeneration. New targeted therapeutics, such as SARM1 inhibitors, and NAD⁺ salvage drugs will help alleviate the dysfunctions affecting cell life and death in neurodegeneration as well as in metabolic diseases and cancer.

Myelofibrosis is one kind of bone marrow blood cancer that gives mainly bone marrow scarring. JAK families include JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2) and they control hematopoiesis and immune cell function. JAK-STAT pathways have the critical roles in the pathogenesis of a variety of autoimmune and inflammatory diseases such as myelofibrosis. The 8 JAK inhibitors are approved by the US FDA for the treatment of various diseases. Abrocitinib, baricitinib, oclacitinib, ruxolitinib, tofacitinib, upadacitinib, fedratinib, and pactrinib with their IC50 values against JAK1, JAK2, JAK3, and TYK2 are included. All approved JAK inhibitors with structural similarities and dissimilarities are summarized. The development story of pacritinib and new design route to overcome intellectual property-related issues by connecting the A ring and C ring to form the macrocyclic compounds like 16 without compromising the binding modes in the hinge region are discussed. By using the powerful ring-closing metathesis (RCM), they designed and synthesized and delivered FDA approved pacritinib. In this short perspective, the chemical structure, physicochemical properties, mechanism of action, drug-interactions, adverse events, and pharmacokinetic profile of pacritinib are summarized. Detailed step by step synthesis of pacritinib is provided. Pacritinib is an orally bioavailable and isoform selective JAK-2 inhibitor for the treatment of patients with myelofibrosis. Detailed metabolism pathway with proper explanation is discussed.

In underdeveloped nations, colorectal carcinogenesis (CRC) is a significant health issue. It is the third most common outcome of cancer death. Despite a variety of therapy options, new medications are needed to lessen the severity of this condition. In the colon, adenomatous polyps are the most common cause of CRC, occurring in 45 percent of cases, particularly in patients over 60 years old. Inflammatory polyps are acquiring popularity in CRC, as well as inflammation appears to exert a function in the disease, according to mounting research. The azoxymethane, dimethyl hydrazine, APC^min/+ mouse model, and a combination of sulfated polysaccharides composed of dextran and sulfated and dimethylhydrazine are among the experimental models used to study CRC in animals. Numerous signal transduction pathways are engaged as CRC progresses. The p53, TGF-β, Delta-Notch, Salvador-Warts-Hippo (SWH), and Kelch-like ECH associated protein 1 pathways are among the key signal transduction pathways. To decide cell destiny, several signalling pathways work in tandem with the death of cell modalities, such as autophagy, necroptosis, and apoptosis. In our lab, we have spent a lot of time looking into the cell signalling and mechanisms of cell death in CRC. The pathogenesis of CRC, as well as the associated cell death and cell signalling pathways, are summarised in this study.

Objective: The present study aimed to investigate the cytotoxic effect of various extracts derived from Abrus precatorius Linn. leaves on rat L6 and human SK-N-MC neuroblastoma cell lines and determine the secondary metabolites responsible for the cytotoxicity of Abrus precatorius. Methods: Successive solvent extraction of A. precatorius leaves was carried out using the Soxhlet apparatus with solvents such as petroleum ether, chloroform, ethyl acetate, and ethanol. HPTLC fingerprinting and LC-MS studies were performed to assess the presence of secondary metabolites, such as flavonoids and phenols, in the ethyl acetate extract. Furthermore, the cytotoxic effect of extracts was tested on rat skeletal muscle cell line L6 and human neuroblastoma cell line SK-N-MC using MTT assay. Results: The total phenolic content of ethyl acetate and ethanol extracts of A. precatorius were 72.67 and 60.73 mg, respectively, of GAE/g dry weight of the extract. The total flavonoid content of ethyl acetate and ethanol extract of A. precatorius were 107.33 and 40.66 mg of Quercetin equivalents/g dry weight of the extract. LCMS analysis demonstrated that the flavonoids in specific Naringenin, Diosmetin, Glycitin, and Genistein might play a prominent role in the cytotoxicity of A. precatorius. The cytotoxicity study revealed that the extracts of A. precatorius were non-toxic to rat L6 myotubes, and the IC50 values of the various extracts, such as APPE, APCH, APEA, and APET, were >100 μg/ml. The extracts exhibited cytotoxic activity against human neuroblastoma SK-N-MC cells, and the IC50 values of APPE, APCH, APEA, APET, and the standard drug “Cisplatin” were >100, >100, 64.88, >100, and 3.72 μg/ml, respectively. Conclusion: It was concluded from the study that the extracts of Abrus precatorius were cytotoxic to neuroblastoma cell lines but non-toxic to normal cell lines. HPTLC and LC-MS studies confirmed that flavonoids in the ethyl acetate extract could be responsible for the biological activity.

Background: Breast cancer is characterized by uncontrolled cell growth in the breast tissue and is a leading cause of death globally. Cytotoxic effects and reduced efficacy of currently used therapeutics insist to look for new chemo-preventive strategies against breast cancer. LKB1 gene has recently been categorized as a tumor suppressor gene where its inactivation can cause sporadic carcinomas in various tissues. Mutations in the highly conserved LKB1 catalytic domain lead to the loss of function and subsequently elevated expression of pluripotency factors in breast cancer. Objective: The utilization of drug-likeness filters and molecular simulation has helped evaluate the pharmacological activity and binding abilities of selected drug candidates to the target proteins in many cancer studies. Methods: The current in silico study provides a pharmacoinformatic approach to decipher the potential of novel honokiol derivatives as therapeutic agents against breast cancer. AutoDock Vina was used for molecular docking of the molecules. A 100 nano second (ns) molecular dynamics simulation of the lowest energy posture of 3'-formylhonokiol- LKB1, resulting from docking studies, was carried out using the AMBER 18. Results: Among the three honokiol derivatives, ligand-protein binding energy of 3' formylhonokiol with LKB1 protein was found to be the highest via molecular docking. Moreover, the stability and compactness inferred for 3'- formylhonokiol with LKB1 are suggestive of 3' formylhonokiol being an effective activator of LKB1via simulation studies. Conclusion: It was further established that 3'- formylhonokiol displays an excellent profile of distribution, metabolism, and absorption, indicating it is an anticipated future drug candidate.

Background: Acute lymphoblastic leukemia (ALL) is the second most common acute leukemia in adults, whose known drug treatments are limited and expensive. Objective: This investigation aimed to investigate the therapeutic potential of anlotinib in B-cell acute lymphoblastic leukemia (B-ALL). Methods: The B-ALL cell lines Nalm-6 and BALL-1 were used to verify the therapeutic potential of anlotinib in BALL. The cell activity was measured by Cell Counting Kit-8. Apoptosis was detected by Annexin V-FITC/PI double staining combined with flow cytometry. Afterward, the binding capacity of anlotinib to the critical protein was predicted by molecular docking, and the protein changes in the related pathways downstream of the target proteins were verified by western blot. Finally, the effect of anlotinib on the survival rate was verified in B-ALL nude mice. Results: Anlotinib inhibited the proliferation of the B-ALL cell lines, Nalm-6, and BALL-1, and promoted apoptosis. Molecular docking results showed that it had the potential binding ability to BTK. Western blot revealed that anlotinib was able to inhibit the phosphorylation of BTK, AKT, and mTOR, thereby inhibiting the proliferation of B-ALL cells. In addition, anlotinib suppressed weight loss and prolonged the survival time of mice. Conclusion: To summarize, anlotinib can inhibit the proliferation of B-ALL and promotes apoptosis by inhibiting the phosphorylation of BTK and AKT, and mTOR.

Background: Colorectal cancer (CRC) is one of the most common tumors globally and a leading cause of cancer-related death. In China, CRC is the third most common cancer type. Sauchinone is known to exhibit anti-tumor and anti-inflammatory activity, but its effects on CRC have not been investigated to-date Objective: To investigate the effects of Sauchinone on CRC development and metastasis and its underlying mechanism( s) of action. Methods: SW480 and HCT116 cells were treated with a range of concentrations of Sauchinone. Cell proliferation was measured using EDU assays and flow cytometry. Results: Treatment with 50 μM Sauchinone decreased the expression of MMP2 and MMP9 and downregulated PD-L1 expression (PD-1/PD-L1) leading to checkpoint inhibition. Sauchinone treatment also enhanced the cytotoxicity of SW840 and HCT116 cells co-cultured with CD8⁺ T cells. The overexpression of PD-L1 rescued the anti-proliferative and cytotoxic effects of Sauchinone in both types. Conclusions: We show that Sauchinone suppresses CRC cell growth through the downregulation of MMP2 and MM9 expression and PD-1/PD-L1 mediated checkpoint inhibition. Collectively, these data highlight the promise of Sauchinone as a future anti-CRC therapeutic.

Background: Oxaliplatin (OXA) is easy to cause sinusoidal obstruction syndrome (SOS), leading to liver injury. Isolinderalactone (ILL), one of the main components of Lindera aggregate, has been reported to have a protecting effect on the liver. However, it is unclear whether ILL has a therapeutic effect on liver injury caused by OXA. This study aims to determine the effect of ILL on the prevention and treatment of OXA-induced liver injury and to provide a basis for the chemotherapy of gastrointestinal tumors. Methods: Intraperitoneal injection of folinic acid, 5-fluorouracil, and OXA was administered on the SOS rat model for 7 weeks. The indexes of liver function were measured by biochemical kit. The ratio of liver weight to body weight was calculated. The pathological analysis of the liver was scored with the SOS scoring standard, fibrosis was evaluated with a four-point scale. The expression of inflammation factors was detected by Real-Time PCR, and the related indexes of IL-6/STAT3 were examined by Western blot analysis. Results: ILL down-regulated the portal vein pressure and alleviated the abnormal liver function of SOS rats and improved the liver lesions. ILL inhibited the SOS by inhibiting IL-6/STAT3. Conclusion: ILL resistance to liver injury through inhibiting IL-6/STAT3 signal pathway.

Background: Due to the lack of effective drug treatment, triple-negative breast cancer (TNBC) is prone to recurrence and metastasis after an operation. As a glycolytic inhibitor, 3-bromopyruvic acid (3-BrPA) can inhibit the proliferation and induce apoptosis of TNBC cells. However, whether it has similar effects in animal models remains unclear. Objective: To observe the effect of 3-BrPA on the growth and glucose metabolism of human TNBC transplanted tumors in nude mice and to investigate the mechanism. Methods: We constructed subcutaneous xenografts of human TNBC in nude mice and treated them with low, medium and high concentrations of 3-BrPA. After 15 days, nude mice were sacrificed to detect hexokinase (HK) activity and adenosine triphosphate (ATP) content in tumor tissues. Hematoxylin-eosin (HE) staining was used to detect the damage of transplanted tumors and liver and kidney in nude mice, which 3-BrPA caused. The expression of c-Myc in tumor tissues was detected by Immunohistochemistry (IHC). Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining was used to detect the apoptosis of tumor tissues. Besides, the expressions of Cytc, Bax, Bcl-2 and Caspase-9 were detected by Western blotting. Results: Compared with the control group, intraperitoneal injection of 3-BrPA inhibited the growth of human TNBC transplant tumors, decreased HK activity and ATP production in tumor tissues, disrupted the tissue structure of transplant tumors, and did not significantly damage liver and kidney tissues. IHC staining and Western blotting showed that 3-BrPA could decrease the expression of c-Myc and Bcl-2, increase the expression of Cyt -c, Bax and Caspase-9 expression and promote apoptosis in tumor tissues. Conclusion: The above data indicate that 3-BrPA inhibits the growth of human TNBC transplanted tumors and promotes their apoptosis. Its anti-cancer mechanism might reduce HK activity by down-regulating c-Myc expression, eventually leading to decreased glycolytic pathway energy production and promoting apoptosis of transplanted tumors.

Background: 2-Amino thiophene derivatives are important compounds not only for their uses in many heterocyclic reactions but also due to their wide range of pharmaceutical and biological activities. Objective: The aim of this work was to explore a number of new heterocyclic derivatives, studying their inhibitions toward cancer cell lines and studying their structure activity relation ship. Methods: Alkylation of 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile was achieved through its reaction with chloroacetone and 2-bromo-1-(4-aryl)ethanone derivatives to give compounds 3 and 11a-c. The produced compoumds were subjected to further heterocylization reactions and cytotoxic evaluation against the three cancer cell lines MCF-7, NCI-H460 and SF-268, together with the normal cell line WI 38. Further evaluations were obtained through studying their inhibitions against cancer cell lines classified according to the disease. Anticancer screening against hepatocellular carcinoma HepG2 and cervical carcinoma HeLa cell lines for all compounds together with the molecular docking of 12c, 12d, 12e and 12f were studied. Results: Anti-proliferative evaluations and inhibitions for all of the synthesized compounds showed that many compounds exhibited high inhibitions. Conclusion: Toward the three cancer cell lines, compounds 3, 5a, 7a, 9a, 9b, 11b, 12b, 12d, 12e, 12f, 14c, 14e, 14f, 15e, 15f, 16e, 16f, 17c, 18b, 22a and 22c were the most cytotoxic compounds. The high activities of some compounds were attributed to the presence of the electronegative CN and or Cl groups within the molecule. Most of the tested compounds exhibited inhibitions higher than the reference doxorubicin toward hepatocellular carcinoma HepG2 and cervical carcinoma HeLa cell lines. The score of binding energy of compounds 12c, 12d, 12e and 12f was close to the reference Foretinib which appeared through the molecular docking results of such compounds.

Introduction: Thiophene derivatives have been widely studied as promising options for the treatment of solid tumors. Previous studies have shown that thiophene derivatives have antileishmanial activity and cytotoxic activity against breast, colon, and ovarian cancer cells. Methods: In our study, we evaluated the anticancer activities of three aminothiophene derivatives: SB-44, SB-83, and SB-200, in prostate and cervical adenocarcinoma cells. Several in vitro methods were performed, including cytotoxicity, clonogenic migration, mutagenic, and cleaved Poly (ADP-ribose) polymerase (PARP) assays and annexin V staining. Results: Significant cytotoxicity was observed in cell lines with IC50 values less than 35 μM (15.38-34.04 μM). All aminothiophene derivatives significantly reduced clone formation but had no effect on cell motility. SB-83 and SB-44 induced a significant increase in the percentage of cells in the sub-G1 phase, while SB-200 derivatives significantly decreased the percentage of S/G2/M as well as induced apoptosis, with an increase of cleaved PARP. SBs compounds also showed significant mutagenic potential. Beyond that, in silico analyses revealed that all three thiophene derivatives fulfilled the criteria for oral druggability, which underscores the potential of using them in anticancer therapies. Conclusion: Our findings show that the thiophene nucleus may be used to treat solid tumors, including prostate cancer and cervical adenocarcinoma.

Introduction: Prostate cancer is the second-leading cause of cancer death in men. Sinularin is a soft coralsderived natural compound that has anticancer activity in many cancer cells. However, the pharmacological action of sinularin in prostate cancer is unclear. Aim: The aim of the study is to examine the anticancer effects of sinularin in prostate cancer cells. Methods: We explored the anticancer effects of sinularin on the prostate cancer cell lines, PC3, DU145, and LNCaP, by MTT, Transwell assay, wound healing, flow cytometry, and western blotting. Results: Sinularin inhibited the cell viability and colony formation of these cancer cells. Furthermore, sinularin inhibited testosterone-induced cell growth in LNCaP cells by downregulating the protein expression levels of androgen receptor (AR), type II 5α-reductase, and prostate-specific antigen (PSA). Sinularin significantly attenuated the invasion and migration ability of PC3 and DU145 cells, with or without TGF-β1 treatment. Sinularin inhibited epithelialmesenchymal transition (EMT) in DU145 cells after 48 h of treatment by regulating the protein expression levels of Ecadherin, N-cadherin, and vimentin. Sinularin induced apoptosis, autophagy, and ferroptosis by regulating the protein expression levels of Beclin-1, LC3B, NRF2, GPX4, PARP, caspase-3, caspase-7, caspase-9, cleaved-PARP, Bcl-2, and Bax. Moreover, intracellular reactive oxygen species (ROS) were increased but glutathione was decreased after sinularin treatment in PC3, DU145 and LNCaP cells. Conclusion: Sinularin regulated the androgen receptor signaling pathway and triggered apoptosis, autophagy, and ferroptosis in prostate cancer cells. In conclusion, the results indicated that sinularin may be a candidate agent for human prostate cancer and need further study for being applied to human.

Introduction: Despite numerous scientific advances, cancer continues to be one of the main causes of death in the world. This situation has driven the search for promising molecules. Lichen substances have been widely described for their pharmacological potential. Objective: The present study evaluated the antitumour potential of a depsidone isolated from Parmotrema concurrens– salazinic acid (SAL) – through in vitro, in vivo and in silico studies. Methods: The molecule was isolated from the acetonic extract of the lichen and recrystallized in acetone. The macrophage J774, sarcoma-180 and MDA-MB-231 cell lines were used for the MTT cytotoxicity assay. The antitumor assay used a murine model (Swiss albino mice) with sarcoma-180. The animals were treated for seven consecutive days with doses of SAL (25 and 50 mg/kg) and 5-fluorouracil (20 mg/kg). Results: Its purity was determined using high-performance liquid chromatography (94%), and its structure was confirmed by H¹ and C¹³ nuclear magnetic resonance. SAL was not considered toxic to cancer cell lines, showing cell viability rates of 79.49 ± 4.15% and 86.88 ± 1.02% for sarcoma-180 and MDA-MB-231, respectively. The tumour inhibition rate was greater than 80% in the animals treated with SAL and 65% for those that received 5-fluorouracil. Simulations of molecular dynamics to estimate the flexibility of the interactions between human thymidylate synthase and derivatives of SAL and 5-fluorouracil revealed that SAL exhibited greater enzymatic interaction capacity, with highly favourable energy, compared to 5-fluorouracil. Conclusion: The present results demonstrate the potential of salazinic acid as a tumour inhibition agent.