Structure –activity relationships and evaluation of esterified diterpenoid alkaloid derivatives as antiproliferative agents

AbstractDiterpenoid alkaloids with remarkable chemical properties and biological activities are frequently found in plants of the generaAconitum,Delphinium, andGarrya. However, little information has been reported on the antiproliferative effects of the diterpenoid alkaloid constituents ofAconitum andDelphinium plants. C-1 and 14 esterifications of delcosine (1) were carried out to provide 39 new diterpenoid alkaloid derivatives (3–14,16–29,3a–7a,9a,13a,13b,14a,14b,16a,17a,24a,35a). Selected compounds (3–14,16–29,3a–7a,9a,13a,13b,14a,14b,16a,17a,24a,35a) were evaluated for antiproliferative activity against three to five human tumor cell lines including triple-negative breast cancer (TNBC) and P-glycoprotein (P-gp)  overexpressing multidrug-resistant (MDR) subline. Several newly synthesized delcosine derivatives (6,7,13,13a,13b) showed substantial suppressive effects against all human tumor cell lines tested. In contrast, the natural alkaloids (1,31,33) showed no effect. Most of the active compounds were delcosine derivatives with two specific substitution patterns —C-1 and C-1,14. In particular, 1-acyldelcosine derivative (5–7) displayed more potency than 1,14-diacyldelcosine derivatives (5a–7a). These acylated alkaloid derivatives caused accumulation of TNBC cells at sub-G1 within 24  h. 1-Acylation of1 appears to be critical for producing antiproliferative activity in this alkaloid class and a means to pr...
Source: Journal of Natural Medicines - Category: Drugs & Pharmacology Source Type: research

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In this study, we used [O2-(2,4-dinitrophenyl)-1-[(4-ethoxycarbonyl)-piperazin-1 yl]-diazene-1-ium-1-2-diolate] (JS-K), a tumor-specific NO-donor to study the reversal of drug resistance in both P-gp- and BCRP-overexpressing human tumor cells. We report here that while JS-K was extremely effective in reversing adriamycin resistance in the P-gp-overexpressing tumor cells (NCI/ADR-RES); it was significantly resistant to BCRP-overexpressing (MCF-7/MX) tumor cells, suggesting that JS-K may be a substrate for BCRP. Using another NO-donor (DETNO), we show that NO directly inhibits the ATP activities of BCRP, inducing significa...
Source: Biomedicine and Pharmacotherapy - Category: Drugs & Pharmacology Source Type: research
In this study, we used [O2-(2,4-dinitrophenyl)-1-[(4-ethoxycarbonyl)-piperazin-1 yl]-diazene-1-ium-1-2-diolate] (JS-K), a tumor-specific NO-donor to study the reversal of drug resistance in both P-gp- and BCRP-overexpressing human tumor cells. We report here that while JS-K was extremely effective in reversing adriamycin resistance in the P-gp-overexpressing tumor cells (NCI/ADR-RES); it was significantly resistant to BCRP-overexpressing (MCF-7/MX) tumor cells, suggesting that JS-K may be a substrate for BCRP. Using another NO-donor (DETNO), we show that NO directly inhibits the ATP activities of BCRP, inducing significa...
Source: Biomedicine and pharmacotherapy = Biomedecine and pharmacotherapie - Category: Drugs & Pharmacology Authors: Tags: Biomed Pharmacother Source Type: research
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Source: Advances in Experimental Medicine and Biology - Category: Research Tags: Adv Exp Med Biol Source Type: research
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Source: Advances in Experimental Medicine and Biology - Category: Research Tags: Adv Exp Med Biol Source Type: research
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Source: Advances in Experimental Medicine and Biology - Category: Research Tags: Adv Exp Med Biol Source Type: research
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Source: Advances in Experimental Medicine and Biology - Category: Research Tags: Adv Exp Med Biol Source Type: research
Abstract Multidrug resistance (MDR) is a key issue accounting for ineffectiveness of cancer chemotherapy. Numerous multifunctional nanocarriers have been developed to increase drug delivery efficacy and inhibit drug efflux for overcoming cancer drug resistance. However, limited success has been achieved in clinic because of nanocarriers' complicated multi-step fabrication procedures and their undesired side toxicity as well as potential immunogenicity. Here, hyaluronic acid (HA) functionalized extracellular vesicles (EVs) are generated as natural vehicles to efficiently deliver doxorubicin (DOX) and reverse MDR. T...
Source: Biomaterials - Category: Materials Science Authors: Tags: Biomaterials Source Type: research
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Source: Food and Chemical Toxicology - Category: Food Science Authors: Tags: Food Chem Toxicol Source Type: research
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Source: Journal of Pharmacy and Pharmacology - Category: Drugs & Pharmacology Authors: Tags: Research Paper Source Type: research
Publication date: October 2019Source: Biomedicine &Pharmacotherapy, Volume 118Author(s): Angelina Sampson, Brian G. Peterson, Kee W. Tan, Surtaj H. IramAbstractMultidrug resistance protein 1 (MRP1/ABCC1) actively transports a variety of drugs, toxic molecules and important physiological substrates across the plasma membrane. It can confer broad-spectrum multidrug resistance and can decrease the bioavailability of many important drugs. Substrates of MRP1 include anti-cancer agents, antibiotics, antivirals, antidepressants and anti-inflammatory drugs. Using calcein as a fluorescent reporter in a high content uptake assay...
Source: Biomedicine and Pharmacotherapy - Category: Drugs & Pharmacology Source Type: research
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