Synthesis and Anticancer Activity of A-Ring-Modified Derivatives of Dihydrobetulin

Толмачева, И. А.; Beloglazova, Yulia; Назаров, М. А.; Gagarskikh, O. N.; Гришко, В. В.

doi:10.3390/ijms24129863

Cited by 3 publications

(1 citation statement)

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“…Although TQ has shown great potency, its clinical trials was suspended recently due to obvious side effects reported in the phase III clinical trial of lung cancer. 28 Therefore, lots of P-gp inhibitors 29–70 with new scaffolds are continuously being developed to enhance activity and selectivity. However, in order to truly obtain clinically applicable sensitizers for resistant tumors, the exploration in this field is still ongoing.…”

Section: Introductionmentioning

confidence: 99%

Discovery of new tricyclic spiroindole derivatives as potent P-glycoprotein inhibitors for reversing multidrug resistance enabled by a synthetic methodology-based library

Yu,

Zeng,

Guan

et al. 2024

RSC Med. Chem.

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Section: Introductionmentioning

confidence: 99%

Discovery of new tricyclic spiroindole derivatives as potent P-glycoprotein inhibitors for reversing multidrug resistance enabled by a synthetic methodology-based library

Yu,

Zeng,

Guan

et al. 2024

RSC Med. Chem.

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Complex Inhibitory Activity of Pentacyclic Triterpenoids against Cutaneous Melanoma In Vitro and In Vivo: A Literature Review and Reconstruction of Their Melanoma-Related Protein Interactome

Moralev,

Zenkova,

Markov

2024

ACS Pharmacol. Transl. Sci.

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Pentacyclic triterpenoids (PTs) are a class of plant metabolites with a wide range of pharmacological activities, including strong antitumor potential against skin malignancies. By acting on multiple signaling pathways that control key cellular processes, PTs are able to exert complex effects on melanoma progression in vitro and in vivo. In this review, we have analyzed the works published in the past decade and devoted to the effects of PTs, both natural and semisynthetic, on cutaneous melanoma pathogenesis, including not only their direct action on melanoma cells but also their influence on the tumor microenvironment and abberant melanogenesis, often associated with melanoma aggressiveness. Special attention will be paid to the molecular basis of the pronounced antimelanoma potency of PTs, including a detailed consideration of the pathways sensitive to PTs in melanoma cells, as well as the reconstruction of the melanoma-related protein interactome of PTs using a network pharmacology approach based on previously published experimentally verified protein targets of PTs. The information collected on the primary targets of PTs was compiled in the Protein Interactome of PTs (PIPTs) database, freely available at http://www.pipts-db.ru/, which can be used to further optimize the mechanistic studies of PTs in the context of melanoma and other malignancies. By summarizing recent research findings, this review provides valuable information to scientists working in the fields related to the evaluation of melanoma pathogenesis and development of PTs-based drug candidates.

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Soloxolone N-3-(Dimethylamino)propylamide Restores Drug Sensitivity of Tumor Cells with Multidrug-Resistant Phenotype via Inhibition of P-Glycoprotein Efflux Function

Moralev,

Salomatina,

Salakhutdinov

et al. 2024

Molecules

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Multidrug resistance (MDR) remains a significant challenge in cancer therapy, primarily due to the overexpression of transmembrane drug transporters, with P-glycoprotein (P-gp) being a central focus. Consequently, the development of P-gp inhibitors has emerged as a promising strategy to combat MDR. Given the P-gp targeting potential of soloxolone amides previously predicted by us by an absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis, the aim of the current study was to experimentally verify their P-gp inhibitory and MDR reversing activities in vitro. Screening of soloxolone amides as modulators of P-gp using molecular docking and cellular P-gp substrate efflux assays revealed the ability of compound 4 bearing a N-3-(dimethylamino)propylamide group to interact with the active site of P-gp and inhibit its transport function. Blind and site-specific molecular docking accompanied by a kinetic assay showed that 4 directly binds to the P-gp transmembrane domain with a binding energy similar to that of zosuquidar, a third-generation P-gp inhibitor (ΔG = −10.3 kcal/mol). In vitro assays confirmed that compound 4 enhanced the uptake of Rhodamine 123 (Rho123) and doxorubicin (DOX) by the P-gp-overexpressing human cervical carcinoma KB-8-5 (by 10.2- and 1.5-fold, respectively (p < 0.05, unpaired t-test)) and murine lymphosarcoma RLS40 (by 15.6- and 1.75-fold, respectively (p < 0.05, unpaired t-test)) cells at non-toxic concentrations. In these cell models, 4 showed comparable or slightly higher activity than the reference inhibitor verapamil (VPM), with the most pronounced effect of the hit compound in Rho123-loaded RLS40 cells, where 4 was 2-fold more effective than VPM. Moreover, 4 synergistically restored the sensitivity of KB-8-5 cells to the cytotoxic effect of DOX, demonstrating MDR reversal activity. Based on the data obtained, 4 can be considered as a drug candidate to combat the P-gp-mediated MDR of tumor cells and semisynthetic triterpenoids, with amide moieties in general representing a promising scaffold for the development of novel therapeutics for tumors with low susceptibility to antineoplastic agents.

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Synthesis and Anticancer Activity of A-Ring-Modified Derivatives of Dihydrobetulin

Cited by 3 publications

References 50 publications

Discovery of new tricyclic spiroindole derivatives as potent P-glycoprotein inhibitors for reversing multidrug resistance enabled by a synthetic methodology-based library

Discovery of new tricyclic spiroindole derivatives as potent P-glycoprotein inhibitors for reversing multidrug resistance enabled by a synthetic methodology-based library

Complex Inhibitory Activity of Pentacyclic Triterpenoids against Cutaneous Melanoma In Vitro and In Vivo: A Literature Review and Reconstruction of Their Melanoma-Related Protein Interactome

Soloxolone N-3-(Dimethylamino)propylamide Restores Drug Sensitivity of Tumor Cells with Multidrug-Resistant Phenotype via Inhibition of P-Glycoprotein Efflux Function

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