Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 21, Issue 13, 2021

Background: Curcumin, a naturally occurring polyphenol, possesses pleiotropic pharmacologic properties, including anti-inflammatory and anti-oxidant activities. Epidemiological evidence suggests that curcumin intake is associated with a reduced risk of Colorectal Cancer (CRC), highlighting the enormous potential of this botanical agent in the prevention and treatment of CRC. Objective: We summarize the anticancer activity of curcumin and its derivatives in CRC. Methods: We conducted a literature review on the therapeutic effects of curcumin and its derivatives in CRC. Results: In this review, a summary of the activities of curcumin in the treatment of CRC regarding its bioavailability, anticancer activity, modes of action, curcumin delivery systems have been provided based on the researches from preclinical experiments. Also, we discuss the therapeutic effects of curcumin derivatives in CRC. The human clinical trials that used curcumin or curcumin derivatives for the treatment of CRC are also highlighted here. Conclusion: Curcumin possesses great potential as a chemopreventive agent in CRC. Moreover, emerging evidence reveals that it can be an effective adjuvant to CRC therapy. To date, few studies have explored the anticolon cancer activity of curcumin formulation and curcumin derivatives in vivo; therefore, more works are needed to confirm their effectiveness. In clinical trials, curcumin treatment protocols (formulation, dose, and duration) vary among studies. However, these trials consistently point out that the compound is well-tolerated and safe, albeit with little consensus on its therapeutic efficacy.

Cancer is an uncontrolled malignant tumor growth taking place in any tissue of the body and attains complex diversity which makes it difficult for oncologists to choose therapeutics. The changes leading to formation of cancerous cells occur due to a series of molecular events. Now scientists are trying to understand the various molecular processes that are involved in the growth of cancers. This article presents a brief account of epigenetics with reference to DNA methylation and histone modification as an important contributor to the formation of cancer cells. Drug targeting the epigenetic regulators has been considered for various types of cancer. The enzymes in DNA methylation and histone modification, FDA approved clinical drugs along with the challenges associated with the development of anti-cancer target based therapeutics are summarized.

Cancer is the deadliest disease worldwide and the development of safer chemical entities to treat cancer is one of the major challenges of medicinal chemistry. The emergence of new cases every year and the development of multiple drug resistance against available molecular entities have turned the focus of researchers towards natural products. Chalcones are pharmacologically active compounds, present in plants, which have been derivatized and screened by many researchers for the treatment of cancer. Chalcones, consist of 1,3-diaryl-2- propen-1-one, is one such class exhibiting broad anticancer activities against various cancerous cell lines. The objective of this review article is to analyze the antitumor activity of the reported chalcones via distinct mechanisms adopted by these molecules underlying their inhibitory activity. The primary focus of this review is to bring the attention of researchers towards the latest and important chalcones and their derivatives having potent anticancer activity adding their possible action of mechanisms against cancerous cell lines The recent literature was surveyed and it was found that chalcone analogs with electron donating groups, indolyl, quinolone, pyrazol-ol, hydroxyaminobenzamide, hydroxamic acid and pyridyl- indole groups have shown promise as potential anticancer agents following various mechanisms. Most chalcones were found to induce significant cell cycle arrest at G2/M phase hence leading to apoptosis. A number of synthetic chalcones exhibited higher efficacy due to their ability of potent tubulin polymerization as well as dynamic enzyme inhibitory activity. This review is an immense compilation of research regarding the mechanism of action of chalcones and their identification as a promising anticancer agent for future drug developments. Thus, this review article would pave the way and provide ample opportunities to design future generations of novel, highly efficacious anticancer molecules with minimal toxicity.

Background: Aromatase, a cytochrome P450 hemoprotein that is responsible for estrogen biosynthesis by conversion of androgens into estrogens, has been an attractive target in the treatment of hormonedependent breast cancer. Design of new steroidal aromatase inhibitors becomes imperative. Objective: Synthesis and biological evaluation of two classes of structurally and functionally diverse D-ring pregnenolone pyrazoles as type I aromatase inhibitors and antiproliferative agents. Methods: Pregnenolone (1) was converted to 3β-hydroxy-21-hydroxymethylidenepregn-5-en-20-one (2), which upon cyclization with phenylhydrazine generated regioisomeric pairs of pyrazoles 4 and 5. Further, Knoevenagel condensation of pregnenolone (1) with 3-oxo-3-phenylpropanenitrile (6) produced 2-benzoyl-3-(3b-hydroxyandrostan- 5-ene-20-ylidene)-but-2-enenitrile (7), which upon cyclization with hydrazine or phenylhydrazine generated the pyrazoles 8 and 9. All new steroidal derivatives were tested for their aromatase inhibition activity using Dibenzylfluorescein (DBF) based fluorescence assay developed by Stresser et al. Antiproliferative activities were measured using Sulforhodamine B assay. The activities were promising and there was a coherence between aromatase inhibitory and antiproliferative activities. Results: The study reveals the immense potential of pregnenolone pyrazoles as aromatase inhibitors for the treatment of breast cancer. Molecular docking studies proved efficient binding of the new steroidal analogs on human placental aromatase. Conclusion: In the overall study, most of the compounds exhibited potential activity for the treatment of hormone dependent breast cancer. Compounds 4c and 4d were found to be the most promising pharmacons. Furthermore, compounds 4c and 4d were applied for their molecular docking study on human placental aromatase to predict their possible binding modes with the enzyme. These studies revealed that such molecules have high scope and potential for further investigation towards the treatment of estrogen dependent breast cancer.

Background: Panax notoginseng Saponins (PNS) is used as a traditional Chinese medicine for ischemic stroke and cardiovascular disease; it has been proven to possess anticancer activity recently. Objective: In this study, we aimed to explore the curative anticancer effect and potential mechanisms of PNS in pancreatic cancer cells. Methods: Pancreatic cancer Miapaca2 and PANC-1 cells were treated with PNS and Gemcitabine (Gem), respectively. Then the cell viability was assessed by CCK-8 assay, cell proliferation was tested by colony formation assay and EdU cell proliferation assay, cell migration and invasiveness were tested by wound healing assay and transwell assay, respectively, and cell apoptosis was detected by flow cytometry. Finally, we detected the expression levels of proteins related to migration, apoptosis and autophagy through Western blotting. Results: PNS not only inhibited the proliferation, migration, invasion and autophagy of Miapaca2 and PANC-1 cells, but also induced apoptosis and promoted chemosensitivity of pancreatic cancer cells to Gem. Conclusion: PNS may exhibit cytotoxicity and increase chemosensitivity of pancreatic cancer cells to Gem by inhibiting autophagy and inducing apoptosis, providing a new strategy and potential treatment option for pancreatic cancer.

Background: High-Risk Human Papillomavirus (HR-HPV) persistent infection is the main cause of cervical cancer and its precancerous lesions. A previous study showed that HPV16 and HPV58 infections were the most common infection types in the local region. Some studies also declared that HPV58 E7 variants increased the risk of cervical cancer among Asian populations. Objective: This study aimed to determine whether the HPV58 E7 T20I (C632T) variant promotes the malignant behavior of cervical cancer cells and the underlying mechanism of the HR-HPV E7 oncoprotein involved in the development of cervical cancer. Methods: CCK-8 and clone formation assays were used to detect cell proliferation ability. Transwell assays and cell wound healing assays were used to evaluate cell migration ability. Targeted knockdown of E2F1 expression using specific siRNA, RT-qPCR and Western blot were performed to assess gene expression changes. A chromatin immunoprecipitation assay was used to verify that E2F1 interacted with the TOP2A promoter region. Results: HPV58 E7 and HPV58 E7M oncoproteins increased the proliferation and migration ability of cervical cancer cells. However, the HPV58 E7 T20I variant did not promote malignant behaviors compared with wildtype HPV58 E7. HPV E7 and E7M oncoproteins increased the expression of TOP2A, BIRC5 and E2F1, and knockdown of HPV E7 decreased their expression. Low E2F1 expression reduced the expression of TOP2A and BIRC5 and inhibited the proliferation and migration ability of cervical cancer cells. E2F1 interacted with the TOP2A gene promoter region to promote its transcriptional expression. Conclusion: The HPV58 E7 T20I variant did not promote malignant behaviors compared with wild-type HPV58 E7. The HR-HPV E7 oncoprotein enhanced the proliferation and migration of cervical cancer cells, which was considered to be due to the HPV E7 oncoprotein, increasing the expression of BIRC5 and TOP2A by upregulating the transcription factor E2F1.

Background: Chlorophytum comosum, popularly known as Spider Ivy, is used as a medicinal plant in traditional Chinese medicine, however, its detailed chemical composition and biological activity are yet unexplored. Objective: To carry out the phytochemical investigation on different parts of Chlorophytum comosum using GCMS/ LC-ESI-MS and evaluation of its antioxidant, hemolytic and antiproliferative potential on breast cancer (MCF-7), lung cancer (A549, H1299) and normal lung (L-132) cell lines. Methods: Chemical constituents from aqueous roots and leaves extracts were identified using LC-ESI-MS/GCMS. The identified compounds were annotated based on the match of mass spectra with the literature using NIST 14 and METLIN databases. Antioxidant activity was studied using DPPH, FRAP and TPC assays. The antiproliferative effects of ethanolic roots and leaves extracts of Chlorophytum comosum were measured by MTT assay on breast cancer (MCF-7), lung cancer (A549 & H1299) and normal lung (L-132) cell lines. The toxicity studies of the extracts were carried out using Hemolysis assay. Results: GC-MS analysis identified 34 metabolites in roots and 17 from leaves, while 17 compounds from roots and 7 from leaves were detected by LC-ESI-MS. Significant antiproliferative effects were observed on the A549 and MCF-7 cancer cell lines with IC50 values ranging from 56.86 μg/ml to 68.68 μg/ml while no marked response was observed against normal cell line L-132. Conclusion: Our study represents the first report on the detailed chemical composition and antiproliferative potential of Chlorophytum comosum against lung and breast cancer cell lines.

Background: The 2-styrylquinoline-3-carboxylate derivatives have been reported as antiproliferative agents. Objective: The aim of the study was to enhance the selectivity of the drug to the cancer cells. The change in pKa value can be the boost point to enhance the selectivity. The selectivity of the drug will enhance concentration in the cancer cells and will reduce the absorption in the non-cancerous cells. Methods: The designed hydrolysis of the ester group was obtained through the reported method to change the physiological properties, which was correlated with the in silico and in vitro selectivity studies. The compounds were characterized through important analytical techniques, moreover, the biological results of all compounds were obtained through in vitro cancer (MCF-7 and K562) and non-cancerous (HFK293) cell line. Results: The synthesized compounds exhibited micromolar inhibition with a higher selectivity than their ester parent compounds, however, the compound showed better activity to the cancer cell, because of the minimal distribution of the drug in the non-cancerous cells. The compound 2f and 2l were found more selective and potent. Conclusion: The designed 2, 4-disubstituted quinoline-3-carboxylic acid derivatives were evaluated in in vitro cancer (MCF-7 and K562) and non-cancerous (HEK293) cell lines. The most concern issue was resolved by changing the pKa value of compounds, which was calculated by the software base study. The selectivity was correlated with the previously reported ester molecules. The synthesized compounds were characterized by important analytical techniques. The unionized/nonpolar form in the acidic cancer tissue environment, which enhances the drug absorption ion in an acidic medium, was also proved through the in vitro results; hence the compound showed better activity to the cancer cells because of the minimal distribution of the drug in the noncancerous cells. The more selective or less toxic anti-cancer compounds 2f and 2l were reported with all relevant experimental results as in silico Quantitative Estimation of Drug-Likeness (QED) and Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET).

Background: Aberrant glycosylation has been recently considered as a major hallmark of cancer. Furthermore, we have reported that aberrant glycosylation, mainly sialylation and fucosylation, plays a major role in oral cancer progression and metastasis. Objective: In the present study, we evaluated the role of tobacco compounds (4-NQO, NNK, Benzopyrene), natural compounds (Curcumin, Butein and Piceatannol) and commonly used chemotherapeutic compound (Cisplatin) on sialylation and fucosylation transcript levels in the tongue cancer cell line (SAS). Methods: The SAS cells were treated with the tobacco compounds, natural compounds and Cisplatin after obtaining their IC50 values using MTT assay. After 24 hr treatment of the compounds, RNA was isolated from the cells and converted to cDNA. RT-qPCR was performed for mRNA expression of glycosylation transcripts. Results: The treatment of tobacco compounds on the SAS cells resulted in increased mRNA levels of ST3GAL1, NEU3, FUT5 and FUT6 in a dose-dependent manner. The treatment of Curcumin and Butein resulted in lower mRNA levels of FUT8, whereas dose-dependent higher mRNA levels of FUT3 were also observed after the treatment of Curcumin. SAS cells exhibited a dose-dependent decrease in ST3GAL2, FUT5 and FUT8 mRNA after Piceatannol treatment. Furthermore, Cisplatin treatment on the SAS cells resulted in increased mRNA levels of FUT3 as the concentration increased from 100 μM to 200 μM. While, treatment of Cisplatin resulted in decreased mRNA levels of ST3GAL2, ST3GAL3, FUT5 and FUT8 in a dose-dependent manner. All together, the data revealed Piceatannol as a potent synergistic for Cisplatin to target the altered glycosylation for better treatment management of tongue carcinoma. Conclusion: The study provides a normal approach of targeting aberrant glycosylation with natural compounds, which may open the possibility of newer therapeutic strategies using natural compounds alone or in combination with other conventional therapies.

Background: Chronic Myeloid Leukemia (CML) is characterized by a reciprocal translocation t(9;22) and forms BCR/ABL1 fusion gene called the Philadelphia chromosome. The therapeutic targets for CML patients mediated with BCR/ABL1 oncogenic are tyrosine kinase inhibitors such as imatinib, dasatinib, and nilotinib. The latter two of which have been approved for the treatment of imatinib-resistant or intolerance CML patients. Mitotic Catastrophe (MC) is one of the non-apoptotic mechanisms initiated in types of cancer cells in response to anti-cancer therapies. Pharmacological inhibitors of G2 checkpoint members or genetic suppression of PLK1, PLK2, ATR, ATM, CHK1, and CHK2 can trigger DNA-damage-stimulated mitotic catastrophe. PLK1 and AURKA/B are anomalously expressed in CML cells, where phosphorylation and activation of PLK1 occur by AURKB at centromeres and kinetochores. Objective: The purpose of this study is to investigate the effect of dasatinib on the expression of genes in MC and apoptosis pathways in K562 cells. Methods: Total RNA was isolated from K-562 cells treated with the IC50 value of dasatinib and untreated cells as a control group. The expression of MC and apoptosis-related genes, was analyzed by the qRT-PCR system. Results: The array-data demonstrated that dasatinib-treated K562 cells significantly caused the decrease of several genes (AURKA, AURKB, PLK, CHEK1, MYC, XPC, BCL2, and XRCC2). Conclusion: The evidence supplies a basis to support clinical researches for the suppression of oncogenes such as PLKs with AURKs in the treatment of types of cancer, especially chronic myeloid leukemia.

Background: Autophagy is a cellular process that plays a role in the destruction of proteins and organelles. It has been shown that impaired autophagic flux triggers canceration, infectious disease, and neurodegenerative diseases. It has been suggested that tumor formation is inhibited by autophagy that reduces oxidative stress and recycles damaged organelles. microRNAs are 17-25 bp in length, single-stranded, and noncoding small RNAs that play roles in the regulation of metabolic gene expression at the post-transcriptional level. Osteosarcoma is an aggressive bone cancer that affects mainly children and adolescents. Objective: The current article aims to profile autophagy-associated miRNAs in osteosarcoma cell lines and to examine the therapeutical potentials of these miRNAs by suppressing their expressions with Adriamycin and Rapamycin. Methods: We used fluidigm dynamic array nanofluidic chip 96.96 for mRNA expression assay in osteosarcoma cell line U2OS. Results: It was probed that after the suppression of autophagy-associated miRNAs by adriamycin and rapamycin, while most of the miRNAs were down-regulated in osteosarcoma cell lines, some miRNAs’ expressions, such as miR-3141, miR-4296, miR-133b, and miR-720, were strikingly increased. Rapamycin and adriamycin, mTOR inhibitors, stir autophagic machinery, which results in decreased cell survival. Conclusion: Together, we propose that the expressions of miR-3141, miR-4296, miR-133b, and miR-720 might exacerbate the pathogenesis of osteosarcoma; therefore, the suppression of these miRNAs with the loss-offunction approaches could be an appropriate strategy that is worth testing in osteosarcoma.

Introduction: In this contribution, a series of alkoxy substituted chalcones were successfully designed, synthesized, spectroscopically characterized and evaluated for their cytotoxicity potential in inhibiting the growth of MCF-7 cells. Objective: In order to investigate the influence between electron density in conjugated π-systems and biological activities, different withdrawing substituents, namely Nitro (NO2), Cyano (C≡N) and trifluoromethyl (CF3) were introduced in the chalcone-based molecular system. Methods: All the derivatives were then tested on MCF-7 cell line using the fluorescence microscopy-based cytotoxicity analyses. Results: The preliminary findings showed that both –NO2 and –CF3 substituents revealed their potential to inhibit the growth of MCF-7 with IC50 values of 14.75 and 13.75 μg/ml, respectively. In addition, the morphological changes of MCF-7 cells were observed in response to alkoxy substituted chalcone treatment through an induction of apoptosis pathway with cell blebbing, phosphatidylserine exposure and autophagic activity with acidification of lysosomal structure. Intermolecular interaction based on in silico investigation on nitro, trifluoromethyl and cyano based chalcones exhibited several types of interactions with tumor necrosis factor receptor (PDB: 1EXT) protein and high hydrogen bond in the molecule-receptor interaction have given significant impact towards their toxicity on MCF-7 cells. Conclusion: Significantly, these types of chalcones exhibited ideal and high potential to be further developed as anti-cancer agents.

Background: Recently multi-component reactions producing pyran and pyridine derivatives acquired a special attention due to their wide range of pharmacological activities, especially therapeutic activities. Through the market, it was found that many pharmacological drugs containing the pyran and pyridine nucleus were known. Objective: We are aiming in this work to synthesize target molecules possess not only anti-tumor activities but also kinase inhibitors. The target molecules were obtained starting from cyclohexane-1,3-dione followed by its heterocyclization reactions to produce anticancer target molecules. Methods: This work demonstrated multi-component reactions of cyclohexan-1,3-dione with aromatic aldehydes and diethylmalonate using triethylamine as a catalyst to give the 7,8-dihydro-4H-chromen-5(6H)-one derivatives 4a-c. The reaction of compounds 4a-c with either of hydrazine hydrate of phenylhydrazine gave the chromeno[2,3-c]pyrazole derivatives 5a-f, respectively. In addition, further heterocyclization reactions were adopted to give the chromeno[3,2-d]isoxazole, chromene-3-carboxamide derivatives. Moreover, the multicomponent reaction of cyclohexan-1,3-dione (1) with either of aromatic aldehydes and diethylmalonate using a catalytic amount of ammonium acetate gave the 1,4,5,6,7,8-hexahydroquinoline derivatives 13a-c. The antiproliferative activities of the synthesized compounds toward the six cancer cell lines namely A549, H460, HT- 29, MKN-45, U87MG, and SMMC-7721 were studied. In addition, the c-Met enzymatic activities and inhibition toward the prostate cancer cell PC-3 were measured. Results: Anti-proliferative evaluations, c-Met enzymatic activities and inhibition toward the prostate cancer cell PC-3 were measured, and the results obtained in most cases indicated that the presence of electronegative Cl group through the molecule favour the inhibitions. Conclusion: The compounds with high anti-proliferative activity towards the cancer cell lines were 4a, 4b, 6d, 6e, 6f, 10e, 10f, 12c, 14e, 14f, 15c, 16d, 16e, 16f, 19c and 20c. Compounds 4b, 6c, 6d, 8b, 10c, 10d, 12b, 13b, 14c, 14d, 15b, 16c, 16d, 17b, 17c, 19b, 20b and 20c exhibited high potency against c-Met kinase and compounds 4a, 4b, 6b, 6c, 6d, 6f, 8b, 8c, 10c, 10d, 10e, 12b, 12c, 13a, 13b, 13c, 14c, 14d, 14e, 14f, 15b, 15c, 16b, 16c, 16d, 17b, 17c, 19c, 19d, 20a, 20b and 20c displayed high inhibitions toward PC-3 cell line.

Background: The growing dissatisfaction with the available traditional chemotherapeutic agents has enhanced the need to develop new methods for obtaining materials with more effective and safe anti-cancer properties. Over the past few years, the usage of metallic nanoparticles has been a target for researchers of different scientific and commercial fields due to their tiny sizes, environment-friendly properties, and a wide range of applications. To overcome the obstacles of traditional physical and chemical methods for the synthesis of such nanoparticles, a new, less expensive, and eco-friendly method has been adopted using natural existing organisms as a reducing agent to mediate the synthesis of the desired metallic nanoparticles from their precursors, a process called green biosynthesis of nanoparticles. Objective: In the present study, zinc-iron bimetallic nanoparticles (ZnFe2O4) were synthesized via an aqueous extract of Boswellia carteri resin mixed with zinc acetate and iron chloride precursors, and they were tested for their anticancer activity. Methods: Various analytic methods were applied for the characterization of the phyto synthesized ZnFe2O4, and they were tested for their anticancer activity against MDA-MB-231, K562, MCF-7 cancer cell lines, and normal fibroblasts. Results: Our results demonstrate the synthesis of cubic structured bimetallic nanoparticles ZnFe2O4 with an average diameter of 10.54 nm. MTT cytotoxicity assay demonstrates that our phyto-synthesized ZnFe2O4 nanoparticles exhibited a selective and potent anticancer activity against K562 and MDA-MB-231 cell lines with IC50 values 4.53 μM and 4.19 μM, respectively. Conclusion: In conclusion, our biosynthesized ZnFe2O4 nanoparticles show a promising, environmentally friendly, and low coast chemotherapeutic approach against selective cancers with a predicted low adverse side effect toward normal cells. Further, in vivo, advanced animal research should be done to execute their applicability in living organisms.