Synthesis and biological evaluation of podophyllotoxin congeners as tubulin polymerization inhibitors

Kamal, Ähmed; Reddy, T. Srinivasa; Polepalli, Sowjanya; Nekkanti, Shalini; Reddy, Velma Ganga; Rao, A. V. Subba; Jain, Nishant; Shankaraiah, Nagula

doi:10.1016/j.bmc.2014.07.031

Cited by 39 publications

(18 citation statements)

References 32 publications

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“…It was associated with a decrease in the polymerized tubulin fraction (Figures and ); similar results were observed with albendazole, a drug that inhibits microtubule polymerization (Aguayo‐Ortiz et al, ; Gutiérrez‐Gutiérrez, Palomo‐Ligas, et al, ; Pérez‐Rangel et al, ). Besides, our results agree with previous findings in mammalian cells, showing that podophyllotoxin‐type lignans affect the expression and stability of polymerized tubulin (Kamal et al, ; Prinz et al, ).…”

Section: Discussionsupporting

confidence: 93%

“…BUR was not able to bind tubulin, any effect on polymerized tubulin was observed, as previously reported (Antúnez‐Mojica et al, ). On the other hand, some works suggest that podophyllotoxin derivatives are colchicine‐site ligands that inhibit microtubule polymerization (Antúnez‐Mojica et al, ; Escudero‐Martínez et al, ; Kamal et al, ); the zones of the interaction of colchicine have been highly biased toward β‐tubulin. Recently, Naresh Kumar Manchukonda and coworkers (2013) reported that the amino acids that are involved in the interaction of colchicine with tubulin from mammal cells are V236, L246, N247, A248, L253, N255, M256, A314, A315, V316, K350, and A352 (Manchukonda et al, ).…”

Section: Discussionmentioning

confidence: 99%

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Identification and molecular characterization of the tubulin‐podophyllotoxin‐type lignans binding site on Giardia lamblia

et al. 2019

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There are several drugs for the treatment of giardiasis; however, there is a tendency for patients to abandon treatment because of drug‐related adverse effects, resulting in relapses, acquired resistance, and higher rates of treatment failure. Recently, we reported some podophyllotoxin‐type lignans from Bursera fagaroides var. fagaroides showing antigiardial activity. In the present work, we demonstrated that 5′‐desmethoxy‐peltatin‐A‐methylether (5‐DES), acetylpodophyllotoxin (APOD), and podophyllotoxin (POD) affect the distribution and staining pattern of microtubular structures on Giardia trophozoites. Virtual screening results revealed that the lignans act via binding in a hydrophobic pocket in the heterodimer interface of tubulin in Giardia. This study provides useful insight to understand the action mechanism of 5DES, APOD, and POD on Giardia lamblia. The optimization of these podophyllotoxin‐type lignans will lead to promising candidates for antigiardial drugs.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Identification and molecular characterization of the tubulin‐podophyllotoxin‐type lignans binding site on Giardia lamblia

et al. 2019

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“…Microtubules are in dynamic equilibrium with tubulin dimers as tubulin is polymerized into microtubules and depolymerized as free tubulin. This dynamic equilibrium is targeted by microtubule disrupting agents [ 52 ], which inhibit the organization of the mitotic spindle and arrest chromosomes in metaphase of mitosis [ 53 ]. The effect of 6MPTOX on the microtubule polymerization by immunofluorescence of α -tubulin was observed in PC3 cells by confocal microscopy.…”

Section: Resultsmentioning

confidence: 99%

Cytotoxic Activity and Chemical Composition of the Root Extract from the Mexican SpeciesLinum scabrellum: Mechanism of Action of the Active Compound 6-Methoxypodophyllotoxin

Alejandre-García

Álvarez

Cardoso-Taketa

et al. 2015

Evidence-Based Complementary and Alternative Medicine

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The cytotoxic activity and the chemical composition of the dichloromethane/methanol root extract of Linum scabrellum Planchon (Linaceae) were analyzed. Using NMR spectra and mass spectrometry analyses of the extract we identified eight main constituents: oleic acid (1), octadecenoic acid (2), stigmasterol (3), α-amyrin (4), pinoresinol (5), 6 methoxypodophyllotoxin (6), coniferin (7), and 6-methoxypodophyllotoxin-7-O-β-D-glucopyranoside (8). By using the sulforhodamine B assay, an important cytotoxic activity against four human cancer cell lines, HF6 colon (IC50 = 0.57 μg/mL), MCF7 breast (IC50 = 0.56 μg/mL), PC3 prostate (IC50 = 1.60 μg/mL), and SiHa cervical (IC50 = 1.54 μg/mL), as well as toward the normal fibroblasts line HFS-30 IC50 = 1.02 μg/mL was demonstrated. Compound 6 (6-methoxypodophyllotoxin) was responsible for the cytotoxic activity exhibiting an IC50 value range of 0.0632 to 2.7433 µg/mL against the tested cell lines. Cell cycle studies with compound 6 exhibited a cell arrest in G2/M of the prostate PC3 cancer cell line. Microtubule disruption studies demonstrated that compound 6 inhibited the polymerization of tubulin through its binding to the colchicine site (binding constant K b = 7.6 × 106 M−1). A dose-response apoptotic effect was also observed. This work constitutes the first investigation reporting the chemical composition of L. scabrellum and the first study determining the mechanism of action of compound 6.

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“…Podophyllotoxin is an antimitotic agent that interferes with viral replication by inhibiting tubulin polymerization, thus preventing spindle formation. This leads to arrest in metaphase and disruption of the cell cycle, triggering necrosis of HPV-infected host cells [35,36]. Podophyllotoxin is useful in treating condylomata acuminata [37].…”

Section: Antimitotic Therapymentioning

confidence: 99%

Advancements in Pharmacotherapy for Noncancerous Manifestations of HPV

Kollipara

Ekhlassi

Downing

et al. 2015

JCM

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Human papillomavirus (HPV) is the most common sexually transmitted disease. Via infection of the basal epithelial cells, HPV causes numerous malignancies and noncancerous cutaneous manifestations. Noncancerous cutaneous manifestations of HPV, including common, plantar, plane, and anogenital warts, are among the most common reasons for an office visit. Although there are various therapies available, they are notoriously difficult to treat. HPV treatments can be grouped into destructive (cantharidin, salicylic acid), virucidal (cidofovir, interferon-α), antimitotic (bleomycin, podophyllotoxin, 5-fluorouracil), immunotherapy (Candida antigen, contact allergen immunotherapy, imiquimod) or miscellaneous (trichloroacetic acid, polyphenon E). The mechanism of action, recent efficacy data, safety profile and recommended regimen for each of these treatment modalities is discussed.

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Synthesis and biological evaluation of podophyllotoxin congeners as tubulin polymerization inhibitors

Cited by 39 publications

References 32 publications

Identification and molecular characterization of the tubulin‐podophyllotoxin‐type lignans binding site on Giardia lamblia

Identification and molecular characterization of the tubulin‐podophyllotoxin‐type lignans binding site on Giardia lamblia

Cytotoxic Activity and Chemical Composition of the Root Extract from the Mexican SpeciesLinum scabrellum: Mechanism of Action of the Active Compound 6-Methoxypodophyllotoxin

Advancements in Pharmacotherapy for Noncancerous Manifestations of HPV

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