Anti-tubulin agents of natural origin: Targeting taxol, vinca, and colchicine binding domains

Naaz, Fatima; Haider, Rafi; Shafi, Syed; Yar, Mohammad Shahar

doi:10.1016/j.ejmech.2019.03.025

Cited by 155 publications

(107 citation statements)

References 106 publications

Supporting

Mentioning

103

Contrasting

Unclassified

Order By: Relevance

“…Prominent examples of tubulin-binding compounds used clinically for cancer treatment include microtubule-stabilizers that inhibit microtubule function by promoting abnormally high levels of tubulin polymerization. Examples of such drugs include paclitaxel (Taxol) and its semisynthetic analogue docetaxel (Taxotere) [17,18]. In contrast, the vinca alkaloids vincristine, vinorelbine, and vinblastine destabilize microtubules and act as microtubule depolymerizers by inhibiting tubulin polymerization [19].…”

mentioning

confidence: 99%

Synthesis and Biological Evaluation of New Antitubulin Agents Containing 2-(3′,4′,5′-trimethoxyanilino)-3,6-disubstituted-4,5,6,7-tetrahydrothieno[2,3-c]pyridine Scaffold

et al. 2020

View full text Add to dashboard Cite

Two novel series of compounds based on the 4,5,6,7-tetrahydrothieno[2,3-c]pyridine and 4,5,6,7-tetrahydrobenzo[b]thiophene molecular skeleton, characterized by the presence of a 3 ,4 ,5 -trimethoxyanilino moiety and a cyano or an alkoxycarbonyl group at its 2-or 3-position, respectively, were designed, synthesized, and evaluated for antiproliferative activity on a panel of cancer cell lines and for selected highly active compounds, inhibition of tubulin polymerization, and cell cycle effects. We have identified the 2-(3 ,4 ,5 -trimethoxyanilino)-3-cyano-6-methoxycarbonyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine derivative 3a and its 6-ethoxycarbonyl homologue 3b as new antiproliferative agents that inhibit cancer cell growth with IC 50 values ranging from 1.1 to 4.7 µM against a panel of three cancer cell lines. Their interaction with tubulin at micromolar levels leads to the accumulation of cells in the G2/M phase of the cell cycle and to an apoptotic cell death. The cell apoptosis study found that compounds 3a and 3b were very effective in the induction of apoptosis in a dose-dependent manner. These two derivatives did not induce cell death in normal human peripheral blood mononuclear cells, suggesting that they may be selective against cancer cells. Molecular docking studies confirmed that the inhibitory activity of these molecules on tubulin polymerization derived from binding to the colchicine site.

show abstract

mentioning

confidence: 99%

Synthesis and Biological Evaluation of New Antitubulin Agents Containing 2-(3′,4′,5′-trimethoxyanilino)-3,6-disubstituted-4,5,6,7-tetrahydrothieno[2,3-c]pyridine Scaffold

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Similar to benzimidazoles, Combretastatin binds at or near the colchicine domain of beta-tubulin [61], whereas Taltobulin binds at or near the vinca domain [62], together providing some diversity in coverage of tubulin domains. Although both inhibitors had more modest effects on B. pahangi , and T. muris adult worms, their overall performance raises interest in better clarifying relative binding affinities to beta-tubulins from mammals and nematodes, effectiveness against benzimidazole resistant-parasitic nematodes, and potency among analogues that exist for each of these inhibitors [63–65].…”

Section: Discussionmentioning

confidence: 99%

De novo identification of toxicants that cause irreparable damage to parasitic nematode intestinal cells

Jasmer

Rosa

Tyagi

et al. 2019

Preprint

View full text Add to dashboard Cite

Efforts to identify new drugs for therapeutic and preventive treatments against parasitic nematodes have gained increasing interest with expanding pathogen omics databases and drug databases from which new anthelmintic compounds might be identified. Here, a novel approach focused on integrating a pan-Nematoda multi-omics data targeted to a specific nematode organ system (the intestinal tract) with evidence-based filtering and chemogenomic screening was undertaken. Based on de novo computational target prioritization of the 3,564 conserved intestine genes in A. suum, exocytosis was identified as a high priority pathway, and predicted inhibitors of exocytosis were tested using the large roundworm (Ascaris suum larval stages), a filarial worm (Brugia pahangi adult and L3), a whipworm (Trichuris muris adult), and the non-parasitic nematode Caenorhabditis elegans. 10 of 13 inhibitors were found to cause rapid immotility in A. suum L3 larvae, and five inhibitors were effective against the three phylogenetically diverse parasitic nematode species, indicating potential for a broad spectrum anthelmintics. Several distinct pathologic phenotypes were resolved related to molting, motility, or intestinal cell and tissue damage using conventional and novel histologic methods. Pathologic profiles characteristic for each inhibitor will guide future research to uncover mechanisms of the anthelmintic effects and improve on drug designs. This progress firmly validates the focus on intestinal cell biology as a useful resource to develop novel anthelmintic strategies.Author summaryThe intestinal cells of parasitic nematodes are not known to regenerate, therefore disruption of essential processes that cause irreparable damage to intestinal cells is expected to promote worm expulsion. To facilitate improved methods of therapy we need to better understand the basic intestinal cell and tissue functions of this critical organ. To that end have undertaken a comprehensive analysis of multi-omics omics data and identify and prioritize intestinal genes/pathways with essential functions and associated drugs and established a foundational model of the STH intestinal system using the large roundworm Ascaris suum to test and validate inhibitors of these functions. We found 10 inhibitors to impacted motility, and seven of those showed severe pathology and an apparent irreparable damage to intestinal cells. Furthermore, five inhibitors were effective against the three phylogenetically diverse parasitic nematode species, indicating potential for a broad spectrum anthelmintics. Our results firmly validate the focus on intestinal cell biology as a useful resource to develop novel anthelmintic strategies.

show abstract

“…They are categorized as either tubulin stabilizing agents or destabilizing agents (Figure 7). While the tubulin stabilizing agents ultimately lead to the polymerization of microtubules by inhibiting depolymerization, the destabilizing agents function by inhibiting polymerization, thereby shortening the microtubules [76]. The indole based alkaloids and their derivatives, such as vincristine, vinblastine, vinorelbine, vinflunine, vindesine belong to the class of polymerization inhibitors that bind to the β-subunit of tubulin at a distinct region called as the vinca-binding site, as shown in Figure 7 [76].…”

Section: Tubulin Inhibitionmentioning

confidence: 99%

“…Moreover, the direct interaction of FC77 with tubulin and inhibition of microtubule dynamics with IC 50 values of 3 nM compared to popular drugs such as paclitaxel and vincristine with IC 50 values of 14 nM and 37 nM, respectively, makes it an attractive microtubule-targeting agent for the treatment of multidrug-resistant cancers [79]. the microtubules [76]. The indole based alkaloids and their derivatives, such as vincristine, vinblastine, vinorelbine, vinflunine, vindesine belong to the class of polymerization inhibitors that bind to the β-subunit of tubulin at a distinct region called as the vinca-binding site, as shown in Figure 7 [76].…”

Section: Tubulin Inhibitionmentioning

confidence: 99%

“…the microtubules [76]. The indole based alkaloids and their derivatives, such as vincristine, vinblastine, vinorelbine, vinflunine, vindesine belong to the class of polymerization inhibitors that bind to the β-subunit of tubulin at a distinct region called as the vinca-binding site, as shown in Figure 7 [76]. Vinorelbine is a semi-synthetic indole based alkaloid extracted from C. roseus (Figure 7).…”

Section: Tubulin Inhibitionmentioning

confidence: 99%

See 1 more Smart Citation

Role of Indole Scaffolds as Pharmacophores in the Development of Anti-Lung Cancer Agents

Dhuguru

Skouta

2020

Molecules

View full text Add to dashboard Cite

Lung cancer is the leading cause of death in men and women worldwide, affecting millions of people. Between the two types of lung cancers, non-small cell lung cancer (NSCLC) is more common than small cell lung cancer (SCLC). Besides surgery and radiotherapy, chemotherapy is the most important method of treatment for lung cancer. Indole scaffold is considered one of the most privileged scaffolds in heterocyclic chemistry. Indole may serve as an effective probe for the development of new drug candidates against challenging diseases, including lung cancer. In this review, we will focus on discussing the existing indole based pharmacophores in the clinical and pre-clinical stages of development against lung cancer, along with the synthesis of some of the selected anti-lung cancer drugs. Moreover, the basic mechanism of action underlying indole based anti-lung cancer treatment, such as protein kinase inhibition, histone deacetylase inhibition, DNA topoisomerase inhibition, and tubulin inhibition will also be discussed.

show abstract

Anti-tubulin agents of natural origin: Targeting taxol, vinca, and colchicine binding domains

Cited by 155 publications

References 106 publications

Synthesis and Biological Evaluation of New Antitubulin Agents Containing 2-(3′,4′,5′-trimethoxyanilino)-3,6-disubstituted-4,5,6,7-tetrahydrothieno[2,3-c]pyridine Scaffold

Synthesis and Biological Evaluation of New Antitubulin Agents Containing 2-(3′,4′,5′-trimethoxyanilino)-3,6-disubstituted-4,5,6,7-tetrahydrothieno[2,3-c]pyridine Scaffold

De novo identification of toxicants that cause irreparable damage to parasitic nematode intestinal cells

Role of Indole Scaffolds as Pharmacophores in the Development of Anti-Lung Cancer Agents

Contact Info

Product

Resources

About