Generic placeholder image

Current Drug Discovery Technologies

Editor-in-Chief

ISSN (Print): 1570-1638
ISSN (Online): 1875-6220

Research Article

Structure-Activity Relationships of Cytotoxic Lactones as Inhibitors and Mechanisms of Action

Author(s): Francisco Torrens* and Gloria Castellano*

Volume 17 , Issue 2 , 2020

Page: [166 - 182] Pages: 17

DOI: 10.2174/1570163816666190101113434

Price: $65

Abstract

Background: Some lactones prevent protein Myb-dependent gene expression.

Objective: The object is to calculate inhibitors of Myb-brought genetic manifestation.

Methods: Linear quantitative structure–potency relations result expanded, among sesquiterpene lactones of a variety of macrocycles (pseudoguaianolides, guaianolides, eudesmanolides and germacranolides), to establish which part of the molecule constitutes their pharmacophore, and predict their inhibitory potency on Myb-reliant genetic manifestation, which may result helpful as leads for antileukaemic therapies with a new mechanism of action.

Results: Several count indices are connected with structure–activity. The α-methylene-γ-lactone ML functional groups increase, whereas OH groups decrease the activity. Hydrophobicity provides to increase cell toxicity. Four counts (ML, number of α, β-unsaturated CO groups, etc.), connected with the number of oxygens, present a positive association, owing to the partial negative charge of oxygen. The s-trans-strans- germacranolide molecule presents maximal potency. The OH groups decrease the potency owing to the positive charge of hydrogen. The numbers of π-systems and atoms, and polarizability increase the potency. Following least squares, every standard error of the coefficients is satisfactory in every expression. The most predictive linear expressions for lactones, pseudoguaianolides and germacranolides are corroborated by leave-group-out cross-validation. Quadratic equations do not make the correlation better.

Conclusion: Likely action mechanisms for lactones are argued with a diversity of functional groups in the lactone annulus, including artemisinin with its uncommon macrocycle characteristic, 1,2,4-trioxane cycle (pharmacophoric peroxide linkage -O1-O2- in endoperoxide ring), which results in the foundation for its sole antimalarial potency.

Keywords: SAR, pharmacophore, bioactiphore, cytotoxic activity, selectivity index, cell viability, Sesquiterpene Lactones (STLs).

Graphical Abstract
[1]
Ali I, Wani WA, Saleem K. Cancer scenario in India with future perspectives. Cancer Ther 2011; 8: 56-70.
[2]
Caballero M, Grau JJ, Blanch JL, et al. Serum vascular endothelial growth factor as a predictive factor in metronomic (weekly) Paclitaxel treatment for advanced head and neck cancer. Arch Otolaryngol Head Neck Surg 2007; 133(11): 1143-8.
[http://dx.doi.org/10.1001/archotol.133.11.1143] [PMID: 18025320]
[3]
Hadzic T, Aykin-Burns N, Zhu Y, et al. Paclitaxel combined with inhibitors of glucose and hydroperoxide metabolism enhances breast cancer cell killing via H2O2-mediated oxidative stress. Free Radic Biol Med 2010; 48(8): 1024-33.
[http://dx.doi.org/10.1016/j.freeradbiomed.2010.01.018] [PMID: 20083194]
[4]
Simons AL, Mattson DM, Dornfeld K, Spitz DR. Glucose deprivation-induced metabolic oxidative stress and cancer therapy. J Cancer Res Ther 2009; 5(Suppl. 1): S2-6.
[http://dx.doi.org/10.4103/0973-1482.55133] [PMID: 20009288]
[5]
Aykin-Burns N, Ahmad IM, Zhu Y, Oberley LW, Spitz DR. Increased levels of superoxide and H2O2 mediate the differential susceptibility of cancer cells versus normal cells to glucose deprivation. Biochem J 2009; 418(1): 29-37.
[http://dx.doi.org/10.1042/BJ20081258] [PMID: 18937644]
[6]
Waugh WN, Trissel LA, Stella VJ. Stability, compatibility, and plasticizer extraction of taxol (NSC-125973) injection diluted in infusion solutions and stored in various containers. Am J Hosp Pharm 1991; 48(7): 1520-4.
[http://dx.doi.org/10.1093/ajhp/48.7.1520] [PMID: 1679294]
[7]
Jujjavarapu SE, Dhagat S, Kurrey V. Identification of novel ligands for therapeutic lipopeptides: daptomycin, surfactin and polymyxin. Curr Drug Targets 2018; 19(13): 1589-98.
[http://dx.doi.org/10.2174/1389450119666171129164932] [PMID: 29189148]
[8]
Eswari JS, Dhagat S, Kaser S, Tiwari A. Homology modeling and molecular docking studies of Bacillomycin and Iturin synthetases with novel ligands for the production of therapeutic lipopeptides. Curr Drug Discov Technol 2018; 15(2): 132-41.
[http://dx.doi.org/10.2174/1570163814666170816112536] [PMID: 28814239]
[9]
Baskaran C, Ramachandran M. Computational molecular docking studies on anticancer drugs. Asian Pac J Trop Biomed 2012; 2: S734-8.
[http://dx.doi.org/10.1016/S2222-1808(12)60254-0]
[10]
Sinha R, Vidyarthi AS, Shankaracharya . A molecular docking study of anticancer drug paclitaxel and its analogues. Indian J Biochem Biophys 2011; 48(2): 101-5.
[PMID: 21682141]
[11]
Mathew A. Insilico docking studies on anticancer drugs for breast cancer in 2009 international association of computer science and information technology-spring conference. IEEE 2009.
[12]
Krishnamoorthy M, Balakrishnan R. Docking studies for screening anticancer compounds of Azadirachta indica using Saccharomyces cerevisiae as model system. J Nat Sci Biol Med 2014; 5(1): 108-11.
[http://dx.doi.org/10.4103/0976-9668.127298] [PMID: 24678207]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy