Human Solid Tumor Cell Research Articles

The Ugi4CR as effective tool to access promising anticancer isatin-based α-acetamide carboxamide oxindole hybrids.

Considering early-stage drug discovery programs, the Ugi four-component reaction is a valuable, flexible, and pivotal tool, facilitating the creation of two new amide bonds in a one-pot fashion to effectively yield the desired α-aminoacylamides. Here, we highlight the reputation of this reaction approach to access number and scaffold diversity of a library of isatin-based α-acetamide carboxamide oxindole hybrids, promising anticancer agents, in a mild and fast sustainable reaction process. The library was tested against six human solid tumor cell lines, among them, non-small cell lung carcinoma, cervical adenocarcinoma, breast cancer and colon adenocarcinoma. The most potent compounds 8d, 8h and 8k showed GI50 values in the range of 1-10 μM.

Palladium nanoparticles for the synthesis of phenanthridinones and benzo[c]chromenes via C-H activation reaction.

In the present work, derivatives of phenanthridine-6(5H)-ones and benzo[c]chromenes were efficiently prepared through an intramolecular C-H bond functionalization reaction catalyzed by photochemically synthesized Pd-PVP nanoparticles. The heterocycles were obtained via intramolecular arylation of the corresponding N-methyl-N-aryl-2-halobenzamide or aryl-(2-halo)benzyl ethers using K2CO3 as base in a mixture of H2O : DMA as solvent without additives or ligands. High yields of the heterocyclic compounds were achieved (up to 95%) using a moderately low catalyst loading (1-5 mol%) under an air atmosphere at 100 °C. The reaction exhibited very good tolerance to diverse functional groups (OMe, Me, t Bu, Ph, OCF3, CF3, F, Cl, -CN, Naph), and both bromine and iodine substrates showed great reactivity. Finally, the in vitro antiproliferative activity of phenanthridine-6(5H)-ones and benzo[c]chromenes was evaluated against six human solid tumor cell lines. The more active compounds exhibit activity in the low micromolar range. 1-Isopropyl-4-methyl-6H-benzo[c]chromene was identified as the best compound with promising values of activity (GI50 range 3.9-8.6 μM). Thus, the benzochromene core was highlighted as a novel organic building block to prepare potential antitumor agents.

Microwave-induced one-pot synthesis of 3-imidazolyl indole clubbed 1,2,3-triazole hybrids as antiproliferative agents and density functional theory study.

Herein, we outline a highly efficient PEG-4000-mediated one-pot three-component reaction for the synthesis of 3-imidazolyl indole clubbed 1,2,3-triazole derivatives (5a-r) at up to 96% yield as antiproliferative agents. This three-component protocol offers the advantages of an environmentally benign reaction, excellent yield, quick response time, and operational simplicity triggered by the copper catalyst under microwave irradiation. All the synthesized compounds were tested for antiproliferative activity against six human solid tumor cell lines, that is, A549 and SW1573 (nonsmall cell lung), HBL100 and T-47D (breast), HeLa (cervix), and WiDr (colon). Among them, six compounds, 5g-j, 5m, and 5p, demonstrated effective antiproliferative action with GI50 values under 10 μM. Furthermore, density functional theory (DFT) calculations were performed for all the synthesized molecules through geometry optimizations, frontier molecular orbital approach, and molecular electrostatic potential (MESP). The theoretical DFT calculation was performed using the DFT/B3LYP/6-31+G (d,p) basis set. Moreover, the biological reactivity of all the representative synthesized molecules was compared with the theoretically calculated quantum chemical descriptors and MESP 3D plots. We also investigated the drug-likeness characteristic and absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction. In general, our approach enables environmentally friendly access to 3-imidazolyl indole clubbed 1,2,3-triazole derivatives as prospective antiproliferative agents.

Modulation of Expression of Drug Metabolizing Enzymes and Augmentation of Anti-cancer Drug Effects: Through Epigenetics and Three-dimensional Cancer Cell Culture Systems

Since commencing my role as a professor in a newly established Department of Pharmacodynamics and Molecular Genetics at the School of Pharmacy, Iwate Medical University, on April 1, 2007, my research has focused on modifying gene expression of cytochrome P-450 (CYP) in established human colon cancer cells. Additionally, I have been investigating methods to enhance the anti-tumor effects of irinotecan (CPT-11) and 5-fluorouracil (5-FU) using epigenetic modifying inhibitors of DNA methyltransferase and histone deacetylase. Treating colon cancer cells with a DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine (DAC), led to elevated expression levels of CYP1B1 and CYP3A4 through demethylation of the promoter regions of related genes. Furthermore, the administration of DAC and the histone deacetylase inhibitor depsipeptide [(DEP), an anti-cancer drug romidepsin] significantly increased the cellular sensitivities of human colon cancer cells to CPT-11 and 5-FU, respectively. Remarkably, DAC treatment also increased colon cancer cell sensitivity to SN-38, an active metabolite of CPT-11, through the suppression of the anti-apoptotic protein Bcl-2. DEP increased colon cancer cell sensitivity to 5-FU in association with increased expressions of tumor-suppressor p21 and major histocompatibility complex class II genes. Another facet of my research is centered around understanding the gene regulatory mechanisms of the CYP1 family through aryl hydrocarbon receptors (AhR)s under glucose-deprivation stress and in three-dimensional (3D) culture systems of human solid tumor cells. In the 3D culture of human liver cancer cells, I found Pregnane X Receptor being implicated in the regulation of CYP1A2, which aligns with the in vivo mode of CYP1A2 expression.

Abstract 6279: CTS2190, a next-generation epigenetic inhibitor for targeting type I PRMT deregulated human tumors

Abstract Methylation of arginine residues by protein arginine methyltransferases (PRMTs) is involved in the regulation of fundamental cellular processes. Type I PRMTs are frequently overexpressed in a variety of human cancers and associated with poor prognosis. Knockout (KO) of Prmt1 in mice results in decreased asymmetric dimethylarginine (ADMA) on cellular proteins, together with increased monomethylarginine (MMA) and symmetric dimethylarginine (SDMA) (Dhar et al., 2013). A structure-based drug discovery effort led to the identification of CTS2190 that showed single-digit nanomolar enzymatic inhibitory activity on type I PRMTs. Here, we report the development and preclinical characterization of CTS2190, a potent, orally bioavailable small molecule type I PRMT inhibitor. CTS2190 demonstrated strong cellular proliferation inhibitory activity in a large, diverse panel of human hematological and solid tumor cell lines across several lineages. In vivo, oral CTS2190 administration once daily resulted in tumor regression in a variety of xenograft (both CDX and PDX) models across different lineages with good tolerance. The anti-tumor activity was dose-dependent and correlated with the inhibition of type I PRMT activity as measured by decrease in ADMA and increase in MMA. In summary, CTS2190 is a promising type I PRMT inhibitor and clinical trial is underway to explore the proof-of-concept anti-tumor benefit for patients. Citation Format: Hui Shi, Xingnian Fu, Qiugeng Ouyang, Jiaxin Huang, Yiqin Wang, Youzhen Wang, Guoliang Xu, Yuan Mi, Haiping Wu. CTS2190, a next-generation epigenetic inhibitor for targeting type I PRMT deregulated human tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6279.

A pan-tumor-siRNA aptamer chimera to block nonsense-mediated mRNA decay inflames and suppresses tumor progression

Immune-checkpoint blockade (ICB) therapy has changed the clinical outcome of many types of aggressive tumors, but there still remain many cancer patients that do not respond to these treatments. There is an unmet need to develop a feasible clinical therapeutic platform to increase the rate of response to ICB. Here we use a previously described clinically tested aptamer (AS1411) conjugated with SMG1 RNAi (AS1411-SMG1 aptamer-linked siRNA chimeras [AsiCs]) to inhibit the nonsense-mediated RNA decay pathway inducing tumor inflammation and improving response to ICB. The aptamer AS1411 shows binding to numerous mouse and human tumor cell lines tested. AS1411 induces tumor cytotoxicity in long incubation times, which allows for the use of the aptamer as a carrier to target the RNAi inhibition to the tumor. The AS1411-SMG1 AsiCs induce a strong antitumor response in local and systemic treatment in different types of tumors. Finally, AS1411-SMG1 AsiCs are well tolerated with no detected side effects.

ATR-mediated CD47 and PD-L1 up-regulation restricts radiotherapy-induced immune priming and abscopal responses in colorectal cancer.

Radiotherapy (RT) of colorectal cancer (CRC) can prime adaptive immunity against tumor-associated antigen (TAA)-expressing CRC cells systemically. However, abscopal tumor remissions are extremely rare, and the postirradiation immune escape mechanisms in CRC remain elusive. Here, we found that irradiated CRC cells used ATR-mediated DNA repair signaling pathway to up-regulate both CD47 and PD-L1, which through engagement of SIRPα and PD-1, respectively, prevented phagocytosis by antigen-presenting cells and thereby limited TAA cross-presentation and innate immune activation. This postirradiation CD47 and PD-L1 up-regulation was observed across various human solid tumor cells. Concordantly, rectal cancer patients with poor responses to neoadjuvant RT exhibited significantly elevated postirradiation CD47 levels. The combination of RT, anti-SIRPα, and anti-PD-1 reversed adaptive immune resistance and drove efficient TAA cross-presentation, resulting in robust TAA-specific CD8 T cell priming, functional activation of T effectors, and increased T cell clonality and clonal diversity. We observed significantly higher complete response rates to RT/anti-SIRPα/anti-PD-1 in both irradiated and abscopal tumors and prolonged survival in three distinct murine CRC models, including a cecal orthotopic model. The efficacy of triple combination therapy was STING dependent as knockout animals lost most benefit of adding anti-SIRPα and anti-PD-1 to RT. Despite activation across the myeloid stroma, the enhanced dendritic cell function accounts for most improvements in CD8 T cell priming. These data suggest ATR-mediated CD47 and PD-L1 up-regulation as a key mechanism restraining radiation-induced immune priming. RT combined with SIRPα and PD-1 blockade promotes robust antitumor immune priming, leading to systemic tumor regressions.

Abstract 3709: Synergistic activity of ABT-263 and ONC201 against solid tumor cell lines is associated with suppression of BAG3, Mcl-1, pAkt, and upregulation of Noxa along with Bax cleavage during apoptosis

Abstract There is an urgent need for the development of novel therapeutic approaches that can address the complex nature of cancer, including resistance to therapy. A major underlying cause of the resistance is the evasion of cell death following anti-cancer drug treatment. A great deal of progress has been made in the discovery and early development of cancer therapeutics that target cell death via the intrinsic or extrinsic cell death pathways. Two such drugs are ABT-263 and ONC201. ABT-263 is a small molecule that targets the pro-apoptotic cell death of tumor cells by blocking the anti-apoptotic function of BCL-XL and BCL-2; ONC201/TIC10 is a first-in-class small molecule originally discovered as a TRAIL-inducing compound. Previous studies have found that a mechanism of resistance to ABT-263 involves upregulation of anti-apoptotic Mcl-1 in ABT-263-treated tumors, while the efficacy of ONC201 is limited by BCL-2 overexpression. Given that ONC201 is known to downregulate Mcl-1 expression and that BCL-2 is a target of ABT-263, the combination of the two drugs has great synergistic potential. ONC201 and ABT-263 been tested in glioblastoma; however, ABT-263 is not able to cross the blood-brain barrier, and the combination of ONC201 and ABT-263 has not been tested in other solid tumors. It remains a gap in the field to test this combination therapy in tissues to which ONC201 and ABT-263 are bioavailable. We explored the combination of TRAIL-inducing compound ONC201/TIC10 and BCL-xl/BCL-2 inhibitor ABT-263 to target the extrinsic and intrinsic apoptotic pathways, respectively, in solid tumor cell lines (N=13) derived from different tissues (colon, prostate, lung, breast, ovary, bladder). We found an IC50 range of 0.83-20.10 μM for ONC201 and 0.06-14.75 μM for ABT-263 among the 13 cell lines. We show that combination of ONC201 and ABT-263 produces a strong synergistic effect leading to tumor cell death across the 1cell line panel, with maximum synergy scores ranging from 13.56-52.23 (scores were calculated using SynergyFinder; scores 0-10 indicate additive effects, while scores >10 indicate synergism), and that the combination is not toxic to human fibroblast cells. We also found that the combination of these two agents resulted in caspase activation and PARP cleavage consistent with induction of apoptosis, and that these effects where over and above individual drug effects. Combination therapy-induced cell death correlated with decreased levels of Mcl-1, BAG3, pAkt, and upregulation of Noxa along with Bax cleavage during apoptosis. Our data provide evidence for synergy from the combination of ONC201 and ABT-263 against human solid tumor cell lines associated with alterations in cell death and pro-survival mediators. The combination of ONC201 and ABT-263 merits further exploration in vivo in a variety of solid malignancies. Citation Format: Francesca R. Di Cristofano, Mara Fong, Lanlan Zhou, Wafik S. El-Deiry. Synergistic activity of ABT-263 and ONC201 against solid tumor cell lines is associated with suppression of BAG3, Mcl-1, pAkt, and upregulation of Noxa along with Bax cleavage during apoptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3709.

Koanolides B-D, new sesquiterpene lactones from Koanophyllon gibbosum

• Three new sesquiterpene lactones (1–3) were isolated from Koanophyllon gibbosum (Asteraceae). • The structures of 1–3 were elucidated using spectroscopic and spectrometric data, including 1D and 2D NMR. • The new compounds exhibit antiproliferative bioactivity with GI 50 values ranging from 1.3 to 16 μM. Three new germacrane-type sesquiterpene lactones, koanolides B–D ( 1 - 3 ) have been isolated from the aerial parts of Koanophyllon gibbosum (Asteraceae), along with the previously reported sesquiterpene lactone koanolide A and the flavonoid eupatorin. The structures of the new compounds were elucidated using spectroscopic and spectrometric data analyses, including 1D and 2D NMR, and by comparison with known spectral data. The antiproliferative activities of the new compounds were evaluated in a panel of six representative human solid tumor cell lines and showed GI 50 values ranging from 1.3 to 16 μM for the new molecules.

Combination Therapy Strategy for Lymphoma Based on Cancer Energy Metabolism of OPB-111077, a Novel Antitumor Agent Inhibiting Mitochondrial Oxidative Phosphorylation

Development of antitumor agents targeting energy metabolism pathways of cancer cells has attracted much attention in recent days. In general, most cancer cells are known to display Warburg effect. Recently, it has been reported that cancer cells exist as heterogeneous groups in the microenvironment surrounding cancer cells and that not only glycolysis but also mitochondrial oxidative phosphorylation (OXPHOS) is important for cancer growth. In addition, many research groups have reported that the acquisition of anticancer drug resistance is caused by metabolic reprogramming from glycolysis to OXPHOS. Therefore, OXPHOS inhibitors could be useful antitumor agents. OPB-111077 is an orally active novel antitumor agent and has the inhibitory effect on mitochondrial OXPHOS. OPB-111077 had the inhibitory effect on mitochondrial respiratory chain complex I which led to the inhibition of energy production and activation of AMPK-mTOR energy stress sensor pathway. In in vitro growth inhibition studies, OPB-111077 showed potent inhibitory effects on the growth of various human blood tumor cell lines derived from leukemia, multiple myeloma and lymphoma with IC 50 values between 18.6 and 525.3 nM, and on the growth of human solid tumor cell lines derived from liver cancer, lung cancer, gastric cancer and breast cancer with IC 50 values ranging from 92.6 to 1727.7 nM. In in vivo studies using SCID mice bearing tumors from human tumor cell lines, daily oral administration of OPB-111077 demonstrated significant antitumor effects against leukemia, lymphoma, liver, gastric and breast cancer cell line-derived tumor, dose-dependently.Here, we report the combination therapy strategy based on the cancer energy metabolism of OPB-111077. We found that OPB-111077 combined with alkylating agent, cyclophosphamide or bendamustine, showed the synergistic effect on xenograft mice model using human diffuse large B‐cell lymphoma (DLBCL) cell line. To clarify this mechanism, we examined the effect of alkylating agents on mitochondrial respiration in vitro using flux analyzer and found that alkylating agents induced OXPHOS nature in the DLBCL cell line. Furthermore, the administration of alkylating agents to DLBCL cell line xenograft model mice followed by mRNA expression analysis of their tumor tissue confirmed that expression of OXPHOS-related markers was induced. These results suggest the administration of alkylating agents induced reprogramming to OXPHOS predominant nature in tumor. The tumor environment is actively reprogrammed to OXPHOS by alkylating agents, and it is changed to a state in which the antitumor effect of OPB-111077 can be more exerted. Thus, alkylating agents enhance the effect of OPB-111077 by tilting glycolytically dominant tumors to OXPHOS dominant. The alkylating agents, cyclophosphamide and bendamustine, are used as standard therapies for lymphoma. OPB-111077 could be treated in a wide range of applications as a combination therapy with the alkylating agents for lymphoma.In clinical, we have confirmed that OPB-111077 has tolerable and controllable toxicity profile of single agent in some advanced cancer patients including DLBCL. Bendamustine and rituximab (BR) therapy is indicated for the treatment of patients who are ineligible for transplantation of relapsed / refractory (R/R) DLBCL. However, there is still a high unmet need for patients with R/R DLBCL due to no standard treatment for transplant‐ineligible patients. We are conducting combination therapy of OPB-111077 with bendamustine and rituximab in Phase 1 clinical trial for R/R DLBCL in Japan. DisclosuresOhi: Otsuka Pharmaceutical Co.,Ltd.: Current Employment. Okuno: Otsuka Pharmaceutical Co.,Ltd.: Current Employment. Tanaka: Otsuka Pharmaceutical Co.,Ltd.: Current Employment. Ohtani: Otsuka Pharmaceutical Co.,Ltd.: Current Employment. OffLabel Disclosure:Compound: OPB-111077 Purpose: Development of novel antitumor agent

The antiproliferative potential of fungi associated with coral and algae collected from a Veracruz Reef System, Gulf of Mexico

Coral reefs are ecosystems with great biodiversity and architectural complexity. Among these, marine fungi constitute one of the least studied groups, despite being potentially an inexhaustible source of bioactive metabolites. For this reason, in this research, we evaluate the antiproliferative activity of 52 fungal strains associated with marine organisms such as algae and coral collected from four islands located in the National Park Sistema Arrecifal Veracruzano, Mexico. One hundred four chloroform:methanol extracts corresponding to the culture broth, and biomass produced from each fungal strain was obtained from these. Subsequently, they were evaluated against six human solid tumor cell lines (HBL-100, HeLa, SW1573, T-47D, WiDr, and A549). The outcome was that six extracts showed activity against at least one cancer cell line. The identity of these fungi corresponded to the genera Nigrospora , Pestalotiopsis , Cladosporium , and Ochroconis according to their morphological and molecular analysis. In this sense, the strain found to have the highest antiproliferative potential [GI 50 (μg mL -1 ) 4.6, 2.5, 8.0, 5.6, 52.0, 4.0] grouped phylogenetically with a species of Nigrospora sp. The preceding confirms that ecosystems provide.

Direct Endoplasmic Reticulum Targeting by the Selective Alkylphospholipid Analog and Antitumor Ether Lipid Edelfosine as a Therapeutic Approach in Pancreatic Cancer.

Simple SummaryPancreatic ductal adenocarcinoma (PDAC), comprising 90–95% of all pancreatic cancers, is one of the deadliest human cancers, with a gloomy prognosis and ~6-month median survival in metastatic tumors. Even patients with resectable tumors show a poor survival rate after surgery. Thus, PDAC represents an unmet therapeutic challenge. The aim of this review was to put into context the conundrum of pancreatic cancer treatment and the advent of a novel therapeutic approach, examining: (a) anatomical factors, demographics, statistics, and therapeutic approaches, affecting tumor detection, treatment, and prognosis; (b) the importance of the endoplasmic reticulum as a major target for pancreatic cancer due to its high abundance and activity in pancreatic cells; (c) the identification of the alkylphospholipid analog edelfosine as a novel drug against pancreatic cancer, showing two outstanding features—selective uptake by tumor tissue, and direct accumulation in the endoplasmic reticulum, leading to persistent endoplasmic reticulum stress and subsequent apoptosis.Pancreatic ductal adenocarcinoma (PDAC), the most common malignancy of the pancreas, shows a dismal and grim overall prognosis and survival rate, which have remained virtually unchanged for over half a century. PDAC is the most lethal of all cancers, with the highest mortality-to-incidence ratio. PDAC responds poorly to current therapies and remains an incurable malignancy. Therefore, novel therapeutic targets and drugs are urgently needed for pancreatic cancer treatment. Selective induction of apoptosis in cancer cells is an appealing approach in cancer therapy. Apoptotic cell death is highly regulated by different signaling routes that involve a variety of subcellular organelles. Endoplasmic reticulum (ER) stress acts as a double-edged sword at the interface of cell survival and death. Pancreatic cells exhibit high hormone and enzyme secretory functions, and thereby show a highly developed ER. Thus, pancreatic cancer cells display a prominent ER. Solid tumors have to cope with adverse situations in which hypoxia, lack of certain nutrients, and the action of certain antitumor agents lead to a complex interplay and crosstalk between ER stress and autophagy—the latter acting as an adaptive survival response. ER stress also mediates cell death induced by a number of anticancer drugs and experimental conditions, highlighting the pivotal role of ER stress in modulating cell fate. The alkylphospholipid analog prototype edelfosine is selectively taken up by tumor cells, accumulates in the ER of a number of human solid tumor cells—including pancreatic cancer cells—and promotes apoptosis through a persistent ER-stress-mediated mechanism both in vitro and in vivo. Here, we discuss and propose that direct ER targeting may be a promising approach in the therapy of pancreatic cancer, opening up a new avenue for the treatment of this currently incurable and deadly cancer. Furthermore, because autophagy acts as a cytoprotective response to ER stress, potentiation of the triggering of a persistent ER response by combination therapy, together with the use of autophagy blockers, could improve the current gloomy expectations for finding a cure for this type of cancer.

Design, Synthesis, and in vitro Evaluation of Tubulin-Targeting Dibenzothiazines with Antiproliferative Activity as a Novel Heterocycle Building Block.

We prepared a series of free NH and N-substituted dibenzonthiazines with potential anti-tumor activity from N-aryl-benzenesulfonamides. A biological test of synthesized compounds (59 samples) was performed in vitro measuring their antiproliferative activity against a panel of six human solid tumor cell lines and its tubulin inhibitory activity. We identified 6-(phenylsulfonyl)-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide and 6-tosyl-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide as the best compounds with promising values of activity (overall range of 2-5.4 μM). Herein, we report the dibenzothiazine core as a novel building block with antiproliferative activity, targeting tubulin dynamics.

In vitro cytotoxicity and neurotoxicity assessment of the alkaloidal constituents derived from Asimina triloba twigs

This study was aimed to evaluate the efficacy and safety of Asimina triloba extracts and its alkaloidal constituents in terms of their cytotoxicity and neurotoxicity towards different cell lines. Six alkaloids (anolobine-9-O-β-d-glucopyranoside, anolobine, norushinsunine, liriodenine, squamolone and coclaurine) were evaluated for their cytotoxic potential in four human solid tumor cell lines (SK-MEL, KB, BT-549, and SK-OV-3). The potential for neurotoxicity was determined using rat cortical neurons. Three extracts, namely a crude methanolic extract, an alkaloid-rich extract, and an acetogenin-rich extract, were also included in the study. The acetogenin-rich extract was the most potent, among all tested extracts, towards SK-MEL, KB, and BT-549 cells with IC50 values in the range of 0.09–0.11 µg/mL. Also, the same extract was found to be significantly toxic to the neurons at 10 µg/mL. The alkaloid-rich extract also showed cytotoxicity, albeit with lower potency, towards SK-MEL, KB, and BT-549 cell lines with IC50 values in the range of 1.7–2.6 µg/mL. Out of the six isolated alkaloids, three alkaloids (anolobine-9-O-β-D-glucopyranoside, norushinsunine, and liriodenine) demonstrated cytotoxic activity. Although the alkaloidal extract did not show any toxicity to neurons up to 10 µg/mL, the pure alkaloids were toxic to the neurons in a concentration-dependent manner. In conclusion, this study underlines the contribution of the alkaloidal constituents in the neurotoxicity and cytotoxicity of A. triloba.

Structural, antioxidant, antiproliferative and in‒silico study of pyridine-based hydrazonyl‒selenazoles and their sulphur isosteres

To evaluate the impact of chalcogen atom type, we performed a comparative study of antioxidant capacity and antiproliferative activity of a focused library of three pyridine-based hydrazonyl-1,3-selenazoles and their sulfur isosteres in five antioxidant assays and in six human solid tumor cell lines, respectively. In-silico calculations were further used to check pharmacokinetic profiles of investigated compounds such as drug-likeness parameters and interaction with water. Generally, selenium compounds appear to be more potent in comparison to sulfur isosteres in the performed essays.

Late‐stage Rh(II)‐catalyzed Nitrene Transfer for the Synthesis of Guaianolide Analogs with Enhanced Antiproliferative Activity

AbstractA set of new guaianolide derivatives (1–9) was obtained from ludartin, achalensolide, and 11,13‐dihydroachalensolide by application of catalytic nitrene transfer reactions. Intermolecular nitrene C(sp3)−H insertions led to the amination of C‐1, C‐2, and C‐10 positions, while alkene aziridination was also observed under these reaction conditions. The antiproliferative activity of natural compounds and their derivatives was evaluated against a panel of human solid tumor cell lines. The results show that an increase in the biological activity was observed following amination at the C‐2 position of Ludartin, thereby demonstrating the interest in late‐stage C−H amination to improve the bioactivity of natural products.

Structure-activity relationship and mechanistic studies for a series of cinnamyl hydroxamate histone deacetylase inhibitors

Histone deacetylases (HDACs) are a family of enzymes that modulate the acetylation status histones and non-histone proteins. Histone deacetylase inhibitors (HDACis) have emerged as an alternative therapeutic approach for the treatment of several malignancies. Herein, a series of urea-based cinnamyl hydroxamate derivatives is presented as potential anticancer HDACis. In addition, structure–activity relationship (SAR) studies have been performed in order to verify the influence of the linker on the biological profile of the compounds. All tested compounds demonstrated significant antiproliferative effects against solid and hematological human tumor cell lines. Among them, 11b exhibited nanomolar potency against hematological tumor cells including Jurkat and Namalwa, with IC50 values of 40 and 200 nM, respectively. Cellular and molecular proliferation studies, in presence of compounds 11a-d, showed significant cell growth arrest, apoptosis induction, and up to 43-fold selective cytotoxicity for leukemia cells versus non-tumorigenic cells. Moreover, compounds 11a-d increased acetylated α-tubulin expression levels, which is phenotypically consistent with HDAC inhibition, and indirectly induced DNA damage. In vitro enzymatic assays performed for 11b revealed a potent HDAC6 inhibitory activity (IC50: 8.1 nM) and 402-fold selectivity over HDAC1. Regarding SAR analysis, the distance between the hydroxamate moiety and the aromatic ring as well as the presence of the double bond in the cinnamyl linker were the most relevant chemical feature for the antiproliferative activity of the series. Molecular modeling studies suggest that cinnamyl hydroxamate is the best moiety of the series for binding HDAC6 catalytic pocket whereas exploration of Ser568 by the urea connecting unity (CU) might be related with the selectivity observed for the cinnamyl derivatives. In summary, cinnamyl hydroxamate derived compounds with HDAC6 inhibitory activity exhibited cell growth arrest and increased apoptosis, as well as selectivity to acute lymphoblastic leukemia cells. This study explores interesting compounds to fight against neoplastic hematological cells.

Synthesis and in vitro study of antiproliferative benzyloxy dihydropyrimidinones.

In this study, we report on antiproliferative benzyloxy dihydropyrimidinones (DHPMs) produced by the Biginelli reaction of benzyloxy benzaldehyde, urea, and diverse 1,3-diones. The reaction was catalyzed by lanthanum triflate and completed within 1-1.5 h, with 74-97% yield. The antiproliferative assay was carried out for all synthesized dihydropyrimidinones against six human solid tumor cell lines. Six compounds showed good antiproliferative activity with GI50 values below 5 μM. Among all the synthesized compounds, the most potent derivative showed good antiproliferative activity against all cell lines with GI50 values in the range of 1.1-3.1 μM. These DHPMs comply with druglikeness. Furthermore, ADMET prediction and the effect of P-glycoprotein on the antiproliferative activity were also studied. Overall, our method allows eco-friendly access to benzyloxy DHPMs as potential anticancer drugs.

Biological Profiling of Semisynthetic C19-Functionalized Ferruginol and Sugiol Analogues

The abietane-type diterpenoids are significant bioactive compounds exhibiting a varied range of pharmacological properties. In this study, the first synthesis and biological investigation of the new abietane-diterpenoid (+)-4-epi-liquiditerpenoid acid (8a) together with several of its analogs are reported. The compounds were generated from the readily available methyl callitrisate (7), which was obtained from callitrisic acid present in Moroccan Sandarac resin. A biological evaluation was conducted to determine the effects of the different functional groups present in these molecules, providing basic structure–activity relationship (SAR) elements. In particular, the ferruginol and sugiol analogs compounds 10–16 were characterized by the presence of a phenol moiety, higher oxidization states at C-7 (ketone), and the hydroxyl, methyl ester or free carboxylic acid at C19. The biological profiling of these compounds was investigated against a panel of six human solid tumor cell lines (HBL-100, A549, HeLa, T-47D, SW1573 and WiDr), four parasitic Leishmania species (L. donovani, L. infantum, L. guyanensis and L. amazonensis) and two malaria strains (3D7 and K1). Furthermore, the capacity of the compounds to modulate gamma-aminobutyric acid type A (GABAA) receptors (α1β2γ2s) is also described. A comparison of the biological results with those previously reported of the corresponding C18-functionalized analogs was conducted.

A Review of High-altitude Hypoxia Adaptation and Hypoxic Solid Tumor

Historically, the Cambrian explosion was a major life evolution event caused by changes of natural environmental oxygen concentration. The use of oxygen was part of the basic survival instinct of higher life, which evolved a complex regulation system in response to variant levels of oxygen concentration. Hypoxia is one of the typical environmental characteristics in plateau areas. After long-term natural selection in hypoxic conditions, numerous species living in plateau areas have evolved unique mechanisms adapted to hypoxia. Recent studies have found that there are some similarities in adaptation to hypoxia between the animals in highland and different types of human solid tumor cells. Herein, we will summarize recent findings about the hypoxia adaptation evolution in high-altitude animals and the characteristics of hypoxic solid tumors, especially the reactive oxygen species responses in hypoxic solid tumors. We believe that deciphering the underlying molecular mechanisms involved in hypoxia adaptation in highland will facilitate the identification of new genes or biomarkers critical for research on hypoxic solid tumors in the future.