Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 20, Issue 1, 2020

Benzene is a six-membered hydrocarbon ring system and if three carbon-hydrogen units of benzene ring are replaced by nitrogen atoms then triazine is formed. Triazines are present in three isomeric forms 1,2,3- triazine, 1,2,4-triazine, and 1,3,5-triazine according to the position of the nitrogen atom. These are weak bases having weaker resonance energy than benzene, so nucleophilic substitution is preferred than electrophilic substitution. Triazine is an interesting class of heterocyclic compounds in medicinal chemistry. Numerous synthetic derivatives of triazine have been prepared and evaluated for a wide spectrum of biological activities in different models with desired findings such as antibacterial, antifungal, anti-cancer, antiviral, antimalarial, antiinflammatory, antiulcer, anticonvulsant, antimicrobial, insecticidal and herbicidal agents. Triazine analogs have exposed potent pharmacological activity. So, triazine nucleus may be considered as an interesting core moiety for researchers for the development of future drugs.

Background: Cancer is a rapidly growing disease and the second most leading cause of death worldwide. Breast, colon, lung, and prostate cancer are the most diagnosed types of cancer among the majority of the population. The prevalence of these cancers is increasing rapidly due to the lack of effective drugs. The search for anti-cancer bioactive components from natural plant sources is gaining immense significance. The aim of the paper is to introduce the readers about the in vitro and in vivo biochemical mechanisms of phenolic acids and flavonoids in these four types of cancers. Methods: A literature search was carried out in databases, including Scopus, SciFinder, Springer, Science direct and Google. The main keywords used were fruits & vegetables, phenolic acids, flavonoids, anticancer, bioavailability, etc. The data obtained were integrated and analyzed. Results: The study revealed the potential molecular mechanisms of phenolic acids and flavonoids, which include the induction of apoptosis, inhibition of cell proliferation, cell-cycle arrest, induction of Poly ADP ribose polymerase cleavage, downregulation of Matrix metalloproteinases-2 and Matrix metalloproteinases-9 activities, decreased levels of B-cell lymphoma-2, etc. Promising effects of phenolic acids and flavonoids have been observed against breast, colon, lung and prostate cancers. Conclusion: The in vitro and in vivo anti-cancer mechanisms of phenolic acids and flavonoids have been revealed in this study. With the knowledge of specific molecular targets and the structural-functional relationship of bioactive compounds, the current review will open a new gateway for the scientific community and provide them a viable option to exploit more of these compounds for the development of novel and efficacious anticancer compounds.

Background: Conventional antitumor Photosensitizers (PS) are normally low toxic in the dark whereas light activation triggers massive cell death (photodynamic therapy, PDT). Objective: To expand the therapeutic potential of PS to dual potency cytocidal agents, taking advantage of the use of bacteriopurpurin for a deeper tissue penetration of light, and suitability of the tetrapyrrolic macrocycle for chemical modifications at its periphery. Methods: Conjugation of a pro-oxidant thiolate Au (I) moiety to the bacteriopurpurin core and evaluation of cytotoxicity in cell culture and in vivo. Results: New water-soluble derivatives showed micromolar cytotoxicity for cultured human tumor cell lines in the dark, including the subline with an altered drug response due to p53 inactivation. Cellular PDT with the selected conjugate, thiolate Au (I)-dipropoxybacteriopurpurinimide (compound 6) with two triphenylphosphine Au fragments, triggered rapid (within minutes) cell death. Damage to the plasma membrane (necrosis) was a hallmark of cell death by compound 6 both in the dark and upon light activation. Furthermore, one single i.v. injection of compound 6 caused retardation of transplanted syngeneic tumors at the tolerable dose. Illumination of tumors that accumulated compound 6 significantly synergized with the effect of 6 in the dark. Conclusion: Complexes of virtually non-toxic, photoactivatable bacteriopurpurin with the gold-containing organic moiety are considered the dual potency antitumor agents, tentatively applicable for intractable tumors.

Background and Objectives: The present study was undertaken to ascertain whether the modulatory effects of blueberries on cell proliferation induced by Swedish snus in the rat forestomach epithelium is mediated via abrogation of the PI3K/Akt/NFΚB signaling axis that regulates cell fate decision. Methods: The transcript and protein expression of genes involved in cell cycle progression and apoptosis, as well as canonical PI3K/Akt/NF-ΚB signaling pathways, were analyzed by qRT-PCR, immunoblotting and ELISA. Expression profiling of noncoding RNAs (ncRNAs) that influence PI3K/Akt/NF-ΚB signaling was undertaken. TUNEL assay was performed using flow cytometry. Results: Administration of snus induced basal cell hyperplasia in the rat forestomach with increased cell proliferation and inhibition of apoptosis. This was associated with the activation of PI3K/Akt/NFΚB signaling. Coadministration of blueberries significantly suppressed snus-induced hyperplasia. Analysis of the molecular mechanisms revealed that blueberries suppress the phosphorylation of Akt, NF-ΚB and IKKβ, prevent nuclear translocation of NF-ΚB and modulate the expression of microRNAs that influence PI3K/Akt/NF-ΚB signaling. Conclusion: Taken together, the results of the current study provide compelling evidence that blueberries exert significant protective effects against snus-induced soft tissue changes in the rat forestomach epithelium mediated by inhibiting key molecular players in the PI3K/Akt/NF-ΚB signaling axis. Long-term studies on the impact of snus exposure on various cellular processes, signaling pathways, and the interplay between genetic and epigenetic mechanisms are however warranted. The results of this investigation may contribute to the development of protection against soft tissue changes induced by smokeless tobacco in the human oral cavity.

Background: Chalcones are naturally occurring compounds found in various plant species which are widely used for the traditional popular treatments. Chalcones are distinguished secondary metabolites reported to display diverse biological activities such as antiviral, antiplatelet, anti-inflammatory, anticancer, antibacterial and antioxidant agents. The presence of a,ß-unsaturated carbonyl group in chalcones is assumed to be responsible for their bioactivity. In addition, heterocyclic compounds having nitrogen such as isoquinolines are of considerable interest as they constitute the core structural element of many alkaloids that have enormous pharmacological activities. Objective: The objective of this study is the synthesis and biological activity of novel chalcones incorporating thiadiazolyl isoquinoline as potential anticancer candidates. Different genetic tools were used in an attempt to know the mechanism of action of this compound against breast cancer. Methods: An efficient one pot synthesis of novel chalcones incorporating thiadiazolyl isoquinoline was developed. The cytotoxic activity of the novel synthesized compounds was performed against four different kinds of cancer cell lines. Results: Among all the tested derivatives, chalcone 3 has the best cytotoxic profile against A549, MCF7, and HeLa cell lines, with IC50s 66.1, 51.3, and 85.1μM, respectively. Molecular docking studies for chalcone 3 revealed that CDK2, and EGFRTK domains have strong binding affinities toward the novel chalcone 3, while tubulin-colchicine-ustiloxin, and VEGFRTK domains illustrated moderate mode of binding. Conclusion: We have developed an efficient method for the synthesis of novel chalcones incorporating thiadiazolyl isoquinoline. All compounds showed better cytotoxicity results against four kinds of cancer cell lines (A549, MCF7, HCT116, and HELA cells). The results depicted that chalcone 3 has a high and promising cytotoxic effect against HELA cell line and the mechanism of cytotoxicity was widely studied through different theoretical and experimental tools. Thus, the newly synthesized derivative 3 can be utilized as a novel chemotherapeutic compound for cervical carcinoma.

Background: Androgen Receptor (AR) is one of the highly explored targets for the treatment of prostate cancer. The emergence of point mutation in the Ligand Binding Domain (LBD) of AR has resulted in the development of resistance against AR antagonist. The point mutation T877A, W741L and F876L confer resistance to flutamide, bicalutamide and enzalutamide respectively. There is no AR antagonist in the present clinical set up without resistance. Hence, our aim in this study is to design a novel molecule to overcome the resistance caused by point mutation. Methods: Here, we developed novel AR antagonist bearing (5-methyl-1H-pyrazol-3-yl)-1, 3,4-oxadiazole core by rational drug design. The test molecules 8a-h were synthesized from the corresponding dihydrazide compounds 7a-h on treatment with phosphorous oxychloride on reflux conditions. The structure of the molecules was confirmed from spectral data such as IR, 1H-NMR, HRMS and 13C-NMR. The synthesized compounds were screened for cytotoxicity in prostate cancer cell lines LNCaP-FGC and PC3. The confirmation of AR mediated activity of the test compounds was confirmed by gene expression study. The interaction of the best active ligands with mutant AR was predicted and drug design was rationalized through docking studies. Results: The test compounds 8a-h were synthesized and the structures were conformed using suitable techniques like IR, 1H-NMR, HRMS and 13C-NMR. Among the tested compounds, 8b and 8d showed potent antiproliferative activity against mutant AR cell lines. Further, these compounds significantly decreased the gene expression of prostate cancer biomarkers. Conclusion: In this study, we have identified a potential hit molecule for AR antagonism that could be further developed to obtain a potent clinical candidate.

Background and Purpose: Although limited by side effects and development of resistance, doxorubicin still represents the most common chemotherapy for breast cancer. Thus, the identification of critical molecules to alleviate doxorubicin resistance is crucial. Here, we provide a molecular rationale for the breast cancer patients potentially benefitting from doxorubicin based on the expression levels of SIRT1, an identified member of longevity genes. Methods: SIRT1-overexpressed and SIRT1-knockdown breast cancer cells were established to investigate the functions of SIRT1 in regulating doxorubicin resistance both in vitro and in vivo. Cell proliferation was analyzed via CCK8 assay, cell apoptosis was studied by TUNEL analysis. Molecule interaction was analyzed through co-immunoprecipitation and immunofluorescence techniques. Sensibility to doxorubicin was assessed in vivo through the nude mice tumorigenicity experiment. Results: First, SIRT1 was found higher-expressed in breast cancer doxorubicin-resistant cells MCF-7/ADR than that in the doxorubicin- sensitive cells MCF-7. Moreover, SIRT1-knockdown MCF-7/ADR cells showed higher susceptible to doxorubicin both in vitro and in vivo models, whereas overexpressing of SIRT1 inhibited this phenotype. Accordingly, SIRT1 was found interacted with Akt, consequently promoted the activity of Akt in MCF-7/ADR cells in vitro and positively correlated with the expression of P-Akt in vivo. Reversing the activity of Akt partially downturned the doxorubicin-resistant effects mediated by SIRT1. Conclusion: This investigation suggested the value of SIRT1 as a biomarker of response to doxorubicin, leading to the development of new tools for the management of breast cancer patients.

Background: Glioblastoma is the most common primary brain tumor in adults with a dismal prognosis. To date, several anticancer agents have been isolated from plants. Helleborus odorus subsp. Cyclophyllus is an endemic plant of the Balcan flora. Herewith, we investigated for the first time, the anti-glioma effect of deglucohellebrin (DGH) extracted from the roots of Helleborus. Methods: We investigated the effect of DGH in U251MG, T98G and U87G glioblastoma cell lines. We selected the T98G cells because of their inherent temozolomide resistance. Results: The IC50 value of reduced viability for DGH was 7x10-5M in U251MG cells, 5x10-5M for the T98G cells and 4x10-5M in U87G cells during 72h treatment. DGH induced G2/M cell cycle arrest, caspace-8 activation and significant mitochondrial membrane depolarization, suggesting the activation of the intrinsic, mitochondrial- dependent apoptotic pathway. DGH and temozolomide induced changes in CDs’ expression in U251MG and T98G cells. In zebrafish, DGH did not induce toxicity or behavioral alterations. Conclusion: The present study is the first to determine the anti-glioma activity of DGH. DGH may be a potent agent for glioblastoma treatment and further studies are needed.

Background: Quinoxaline-1,4-dioxide (QNX) derivatives are synthetic heterocyclic compounds with multiple biological and pharmacological effects. Objective: In this study, we investigated the oxidative status of quinoxaline-1,4-dioxides derivatives in modulating melanoma and glioma cell lines, based on previous results from the research group and their capability to promote cell damage by the production of Reactive Oxygen Species (ROS). Methods: Using in vitro cell cultures, the influence of 2-amino-3-cyanoquinoxaline-1,4-dioxide (2A3CQNX), 3- methyl-2-quinoxalinecarboxamide-1,4-dioxide (3M2QNXC) and 2-hydroxyphenazine-1,4-dioxide (2HF) was evaluated in metabolic activity, catalase activity, glutathione and 3-nitrotyrosine (3-NT) quantitation by HPLC in malignant melanocytes (B16-F10, MeWo) and brain tumor cells (GL-261 and BC3H1) submitted to radiotherapy treatments (total dose of 6 Gy). Results: 2HF increased the levels of 3-NT in non-irradiated MeWo and glioma cell lines and decreased cell viability in these cell lines with and without irradiation. Conclusion: Quinoxaline-1,4-dioxides derivatives modulate the oxidative status in malignant melanocytes and brain tumor cell lines and exhibited a potential radiosensitizer in vitro action on the tested radioresistant cell lines.