scholarly journals Effective generation of glucosylpiericidins with selective cytotoxicities and insights into their biosynthesis

2021 ◽  
Author(s):  
Zengzhi Liu ◽  
Fei Xiao ◽  
Siqi Cai ◽  
Chunni Liu ◽  
Huayue Li ◽  
...  
Keyword(s):  
Natural Products ◽  
Cell Line ◽  
Cancer Cell Line ◽  
Wide Distribution ◽  
Solid Cancer ◽  
Bioactive Natural Products ◽  
Drug Candidates ◽  
Hct 116

Exploring unknown glycosyltransferases (GTs) is important for compound structural glycodiversification during the search for drug candidates. Piericidin glycosides have been reported to have potent bioactivities; however, the GT responsible for piericidin glucosylation remains unknown. Herein, BmmGT1, a macrolide GT with broad substrate selectivity and isolated from Bacillus methylotrophicus B-9987, was found to be able to glucosylate piericidin A1 in vitro. Next, the codon-optimized GT gene, sbmGT1, which was designed based on BmmGT1, was heterologously expressed in the piericidin producer Streptomyces youssoufiensis OUC6819. Piericidin glycosides were thus significantly accumulated, leading to the identification of four new glucopiericidins (compounds 3, 4, 6, 7). Furthermore, using BmmGT1 as the probe, GT1507 was identified in the genome of S. youssoufiensis OUC6819 and demonstrated to be associated with piericidin glucosylation; the overexpression of this gene led to the identification of another new piericidin glycoside, N-acetyl glucosamine-piericidin (compound 8). Compounds 4, 7, and 8 displayed cytotoxic selectivity toward A549, A375, HCT-116, and HT-29 solid cancer cell line over THP-1 lymphoma cell line. Moreover, database mining of GT1507 homologs revealed their wide distribution in bacteria, mainly in those belonging to the High GC Gram+ and Firmicutes -clades, thus representing the potential for identification of novel tool enzymes for compound glycodiversification. IMPORTANCE Numerous bioactive natural products are appended with sugar moieties, and are often critical for their bioactivities. Glycosyltransferases (GTs) are powerful tools for the glycodiversification of natural products. Although piericidin glycosides display potent bioactivities, the GT involved in glucosylation is unclear. In this study, five new piericidin glycosides (compounds 3, 4, 6, 7, and 8) were generated following the overexpression of GT-coding genes in a piericidin producer. Three of them (compounds 4, 7 and 8) displayed cytotoxic selectivity. Notably, GT1507 was demonstrated to be related to piericidin glucosylation in vivo. Furthermore, mining of GT1507 homologs from the GenBank database revealed their wide distribution across numerous bacteria. Our findings would greatly facilitate the exploration of GTs to glycodiversify small molecules in the search of drug candidates.

scholarly journals Toxicity and Antitumor Activity of a Thiophene–Acridine Hybrid

Molecules ◽  
2019 ◽  
Vol 25 (1) ◽  
pp. 64 ◽  
Author(s):  
Thaís Lisboa ◽  
Daiana Silva ◽  
Sâmia Duarte ◽  
Rafael Ferreira ◽  
Camyla Andrade ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Cell Line ◽  
Cancer Cell ◽  
Cancer Cell Line ◽  
Leukemia Cell Line ◽  
Zebrafish Embryos ◽  
Cell Line Hela ◽  
Hct 116

The antitumor effects of thiophene and acridine compounds have been described; however, the clinical usefulness of these compounds is limited due to the risk of high toxicity and drug resistance. The strategy of molecular hybridization presents the opportunity to develop new drugs which may display better target affinity and less serious side effects. Herein, 2-((6-Chloro-2-methoxy-acridin-9-yl)amino)-5,6,7,8-tetrahydro-4H-cyclohepta[b]-thiophene-3-carbonitrile (ACS03), a hybrid thiophene–acridine compound with antileishmanial activity, was tested for toxicity and antitumor activity. The toxicity was evaluated in vitro (on HaCat and peripheral blood mononuclear cells) and in vivo (zebrafish embryos and acute toxicity in mice). Antitumor activity was also assessed in vitro in HCT-116 (human colon carcinoma cell line), K562 (chronic myeloid leukemic cell line), HL-60 (human promyelocytic leukemia cell line), HeLa (human cervical cancer cell line), and MCF-7 (breast cancer cell line) and in vivo (Ehrlich ascites carcinoma model). ACS03 exhibited selectivity toward HCT-116 cells (Half maximal inhibitory concentration, IC50 = 23.11 ± 1.03 µM). In zebrafish embryos, ACS03 induced an increase in lactate dehydrogenase, glutathione S-transferase, and acetylcholinesterase activities. The LD50 (lethal dose 50%) value in mice was estimated to be higher than 5000 mg/kg (intraperitoneally). In vivo, ACS03 (12.5 mg/kg) induced a significant reduction in tumor volume and cell viability. In vivo antitumor activity was associated with the nitric oxide cytotoxic effect. In conclusion, significant antitumor activity and weak toxicity were recorded for this hybrid compound, characterizing it as a potential anticancer compound.

A Novel Triazole Derivative Drug Presenting In Vitro and In Vivo Anticancer Properties

2018 ◽  
Vol 18 (17) ◽  
pp. 1483-1493
Author(s):  
Ricardo Imbroisi Filho ◽  
Daniel T.G. Gonzaga ◽  
Thainá M. Demaria ◽  
João G.B. Leandro ◽  
Dora C.S. Costa ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Line ◽  
Cancer Cell ◽  
Cancer Cell Line ◽  
Hepatic Function ◽  
Anticancer Properties ◽  
Mcf 7

Background: Cancer is a major cause of death worldwide, despite many different drugs available to treat the disease. This high mortality rate is largely due to the complexity of the disease, which results from several genetic and epigenetic changes. Therefore, researchers are constantly searching for novel drugs that can target different and multiple aspects of cancer. Experimental: After a screening, we selected one novel molecule, out of ninety-four triazole derivatives, that strongly affects the viability and proliferation of the human breast cancer cell line MCF-7, with minimal effects on non-cancer cells. The drug, named DAN94, induced a dose-dependent decrease in MCF-7 cells viability, with an IC50 of 3.2 ± 0.2 µM. Additionally, DAN94 interfered with mitochondria metabolism promoting reactive oxygen species production, triggering apoptosis and arresting the cancer cells on G1/G0 phase of cell cycle, inhibiting cell proliferation. These effects are not observed when the drug was tested in the non-cancer cell line MCF10A. Using a mouse model with xenograft tumor implants, the drug preventing tumor growth presented no toxicity for the animal and without altering biochemical markers of hepatic function. Results and Conclusion: The novel drug DAN94 is selective for cancer cells, targeting the mitochondrial metabolism, which culminates in the cancer cell death. In the end, DAN94 has been shown to be a promising drug for controlling breast cancer with minimal undesirable effects.

scholarly journals In vitro antineoplastic activity in triple-negative breast cancer cell line and in vivo

2014 ◽  
Vol 8 (Suppl 4) ◽  
pp. P22
Author(s):  
Klesia Madeira ◽  
Murilo Cerri ◽  
Renata Daltoé ◽  
Alice Herlinger ◽  
João Filho ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Line ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cell Line ◽  
Triple Negative ◽  
Cancer Cell Line

Analysis on Homoeopathic Preparation of Asterias Rubens for Evaluating Anti Breast Cancer Cell Line using Similia Principle

2020 ◽  
Vol 11 (SPL4) ◽  
pp. 805-808
Author(s):  
Ravikumar Raju ◽  
Teja ◽  
Sravanathi P ◽  
Muthu Babu K
Keyword(s):  
Breast Cancer ◽  
Cell Line ◽  
Cancer Cell ◽  
Cancer Cell Line ◽  
In Vitro Study ◽  
In Vivo Studies ◽  
Asterias Rubens ◽  
Mcf 7

Breast cancer is the subsequent foremost reason of cancer death in a woman and ranks as the primary foremost reason of death in India. In its conduct, several measures and recommendation are considered. Homoeopathic medicines are one of the part of a corresponding, and another medicine is utilized for the treatment of cancer. The main purpose of the investigation is to evaluate the anticancer action of homoeopathic arrangements of Asterias rubens  on the basis of the similia principle. We directed an in vitro study using MTT assay to control the result of ultra diluted homoeopathic preparation in contradiction of two human breast glandular cancer cell lines(MCF-7 and MDA-MD- 231), frequently used for the breast cancer treatment, by testing the feasibility of breast cancer (MCF-7 and MDA-MD-231) cell line, with various attenuations of Asterias rubens  at 24 hrs. Multiple comparisons between tested reagents at different concentrations confirmed the significance of the said results. At a dilution of 1:25 6CH and 30CH potency shown superior activity on MCF-7 and no such significant changes on MDA-MD-231 at any dilutions As it fails to offer estrogen receptor(ER) Also progesterone receptor (PR) expression, and also HER2 (human epidermal development variable receptor2) so continuously a triple-negative breast cancer it will be a hostility manifestation for breast cancer with restricted medicine choices. However, further potency needs to be tested. These preliminary significant results warrant further in vitro and in vivo studies to estimate the possible of Asterias rubens  a medicine to treat breast cancer.

scholarly journals Jaceidin Flavonoid Isolated from Chiliadenus montanus Attenuates Tumor Progression in Mice via VEGF Inhibition: In Vivo and In Silico Studies

Plants ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1031 ◽  
Author(s):  
Sameh S. Elhady ◽  
Enas E. Eltamany ◽  
Amera E. Shaaban ◽  
Alaa A. Bagalagel ◽  
Yosra A. Muhammad ◽  
...  
Keyword(s):  
Cell Line ◽  
Cancer Cell ◽  
In Silico ◽  
Cancer Cell Line ◽  
Control Group ◽  
Phytochemical Study ◽  
Aerial Parts ◽  
In Silico Studies

Phytochemical study of Chiliadenus montanus aerial parts afforded six compounds; Intermedeol (1), 5α-hydroperoxy-β-eudesmol (2), 5,7-dihydroxy-3,3’,4’-trimethoxyflavone (3), 5,7,4’-trihydroxy-3,6,3’-trimethoxyflavone (jaceidin) (4), eudesm-11,13-ene-1β,4β,7α-triol (5) and 1β,4β,7β,11-tetrahydroxyeudesmane (6). These compounds were identified based on their NMR spectral data. The isolated compounds were tested for their cytotoxicity against liver cancer cell line (HepG2) and breast cancer cell line (MCF-7). Jaceidin flavonoid (4) exhibited the highest cytotoxic effect in vitro. Therefore, both of jaceidin and C. montanus extract were evaluated for their in vivo anti-tumor activity against Ehrlich’s ascites carcinoma (EAC). Compared to control group, jaceidin and C. montanus extract decreased the tumor weight, improved the histological picture of tumor cells, lowered the levels of VEGF and ameliorate the oxidative stress. Molecular docking and in silico studies suggested that jaceidin was a selective inhibitor of VEGF-mediated angiogenesis with excellent membrane permeability and oral bioavailability.

Cheminformatics techniques in antimalarial drug discovery and development from natural products 1: basic concepts

2019 ◽  
Vol 4 (7) ◽  
Author(s):  
Samuel Egieyeh ◽  
Sarel F. Malan ◽  
Alan Christoffels
Keyword(s):  
Natural Products ◽  
Drug Development ◽  
Antimalarial Drug ◽  
Drug Discovery And Development ◽  
Drug Candidates ◽  
Structure Activity ◽  
Preclinical And Clinical Studies ◽  
Research Cost

Abstract A large number of natural products, especially those used in ethnomedicine of malaria, have shown varying in vitro antiplasmodial activities. Facilitating antimalarial drug development from this wealth of natural products is an imperative and laudable mission to pursue. However, limited manpower, high research cost coupled with high failure rate during preclinical and clinical studies might militate against the pursuit of this mission. These limitations may be overcome with cheminformatic techniques. Cheminformatics involves the organization, integration, curation, standardization, simulation, mining and transformation of pharmacology data (compounds and bioactivity) into knowledge that can drive rational and viable drug development decisions. This chapter will review the application of cheminformatics techniques (including molecular diversity analysis, quantitative-structure activity/property relationships and Machine learning) to natural products with in vitro and in vivo antiplasmodial activities in order to facilitate their development into antimalarial drug candidates and design of new potential antimalarial compounds.

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