Current advances of tubulin inhibitors as dual acting small molecules for cancer therapy

Arnst, Kinsie E.; Banerjee, Souvik; Chen, Hao; Deng, Shanshan; Hwang, Dong-Jin; Li, Wei; Miller, Duane D.

doi:10.1002/med.21568

Cited by 106 publications

(98 citation statements)

References 215 publications

(462 reference statements)

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“…During cancer treatment, many cancers initially respond well to chemotherapy but subsequently lead to acquired resistance such that more than 90% of patients with metastatic cancer either fail to respond or relapse from chemotherapeutics. To address all these issues, various efforts have been invested to elucidate both on inherent and acquired MDR mechanisms [7].…”

Section: Barriers In Current Cancer Therapymentioning

confidence: 99%

Antiproliferative effects on tumor cells of the synthesized gold nanoparticles against Hep2 liver cancer cell line

R¹,

Iyer²

2020

Egypt Liver Journal

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Background: Currently, nanomaterials (NMs) research and development is at a fastest pace due to the enhanced implication in different areas of applications. The synthesis of such NMs through biosynthesis methods is gaining much importance because of low cost involved and environment-friendly approach. In this present study, the nanoparticles (NPs) are synthesized using a medicinal plant, with anticancer properties so as to incorporate the therapeutic activity within the NPs, such that the NPs will have the attributes of NMs alongside the phytoactivity. Results: The synthesis of gold nanoparticles (AuNPs) using Graviola, the fruit of Annona muricata (Ramaphal fruit) commonly referred as Mullu seetha fruit (Tamil), was successfully carried out. The initial confirmations of the NPs were using UV-vis spectra, which showed the characteristic peak for the NPs. HRSEM analysis gave an insight on the size and morphology of the NPs. The zeta potential was measured to check the stability of the NPs. The cytotoxicity was carried out in VERO cell line and anticancer study in Hep2 liver cancer cell line. The surface plasmon resonance (SPR) band showed the characteristic peak at 536 nm for the AuNPs. In SEM micrographs, the size was ranging between 20 and 30 nm, on an average of 15 nm with spherical morphology. On the various tested concentrations in VERO cell line, the nanoparticles were non-toxic to the cells. The anticancer study gave an IC50 value at 10.94 μg/ml. Conclusions:The NPs showed anticancer activity in treated Hep2 liver cancer cell line and as well as commendable non-toxic effect on normal VERO cell line. The results pose a positive impact to expand further studies in the development of potential drug molecules to tackle the disease of interest.

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Section: Barriers In Current Cancer Therapymentioning

confidence: 99%

Antiproliferative effects on tumor cells of the synthesized gold nanoparticles against Hep2 liver cancer cell line

R¹,

Iyer²

2020

Egypt Liver Journal

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“…Arrest in mitosis was confirmed using phospho‐histone 3 staining that revealed increase in the fraction of mitotic cells from 5.2±2.4 % (DMSO‐treated cells) to 62.5±15.1 % and 19.8±6.9 % in the presence of 10 μ m 4 a and 5 b , respectively (Figure f and Figures S6–7). Tubulin polymerization is amenable to modulation by small molecules and interference with microtubule dynamics leads to mitotic arrest. Because the CPA revealed similarity of the fingerprints to the tubulin targeting agents fenbendazole and tubulexin A (Figure b), we analyzed the influence of benzo‐sulfonamides 4 a and 5 b on in vitro tubulin polymerization.…”

Section: Methodsmentioning

confidence: 99%

A Scaffold‐Diversity Synthesis of Biologically Intriguing Cyclic Sulfonamides

Zimmermann

Akbarzadeh

Otte

et al. 2019

Chemistry A European J

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A" branching-folding" synthetic strategy that affords arange of diversecyclic benzo-sulfonamide scaffolds is presented. Whereasd ifferent annulation reactions on common ketimine substrates build the branching phase of the scaffold synthesis, ac ommon hydrogenative ringexpansion method, facilitated by an increase of the ringstrain during the branching phase, led to sulfonamides bearingm edium-sized rings in af olding pathway.C ell paintinga ssay was successfullye mployed to identify tubulin targeting sulfonamides as novel mitotic inhibitors. Supporting information and the ORCID identification number(s) for the author(s) of this articlecan be found under: https://doi.org/10.Scheme2.Abranching pathwaytoc yclic sulfonamides by annulationa nd addition reactions of N-sulfonyl ketimines. DABCO = 1,4-diazabicyclo[2.2.2]octane.Scheme3.Ring-expansion and modulationr eactions through palladium-mediatedheterogeneoush ydrogenation/hydrogenolysis.Conditions:i )10mol %P d/ C, EtOH/EtOAc,1 atm H 2 ;ii) 14 mol %P d/C, EtOH/EtOAc, 7.5 atm H 2 ;i ii)Pearlman'sc atalyst (20 wt %.,9mol %), MeOH/EtOAc,2h; iv) aq. NaOH/THF/MeCN, 19 h; v) first,( COCl) 2 or SOCl 2 in CHCl 3 ,6 08C; then, corresponding amine in THF at 0 8C; vi)Pd(OH) 2 /C, H 2 ;v ii)10mol %P d/C, 7atm H 2 ,16h;v iii)Et 3 N, CDI, MeCN,1 6h;ix) 10 mol %P d/CH 2 ,EtOH (+ EtOAc for 22 d). For 22a:a dditional step of DMP/NaHCO 3 ,DCM 08 C, 3h;x )NaB(OAc) 3 H, corresponding amine, 4 MS, 1,2-DCE,16-48h.

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“…Microtubules along with microfilaments and intermediate filaments form the cytoskeleton of cell which regulates cell growth, movement and homeostasis. [1][2][3][4] Alterations in the expression of tubulin isotypes, microtubule-associated proteins (MAPs) and the post-translational modifications of tubulin lead to a wide variety of cancers and at the same time these changes are also known to influence drug resistance. [4,5] In this context it is worthy to mention that increased acetylation of α tubulin has been observed in cancer.…”

Section: Introductionmentioning

confidence: 99%

“…In this regard, many small molecules have emerged as potential cancer treatment strategies as they are less expensive and more convenient to administer. [3,7,[9][10][11][12][13][14] The most well-known anti mitotic drug, Taxol, has been found to stabilize microtubule polymerization,thereby causing defects in mitotic spindle assembly, chromosome segregation, cell division and also can activate non-cancerous cells of the immune system all of which leads to cancer inhibition. [15][16][17][18] In our laboratory, the mechanism of action of a small molecule based on pyrimidine indole hybrid (PIH (P)) structure was delineated and found to inhibit ciliogenesis by inhibiting the polymerization of tubulin subunits.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of a Tubulin‐Targeted Pyrimidine Indole Hybrid Molecule as an Anticancer Agent

et al. 2020

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Several small molecules targeting microtubule dynamics have been developed because microtubules are considered to be one of the most successful cancer chemotherapeutic targets. In this regard, taxol is most worthy to mention which stabilizes microtubule polymer thereby causing defectsinmitotic spindle assembly, chromosome segregation and cell division resulting in cancer inhibition. In this direction, we have earlier reported a small molecule called Pyrimidine-Indole-Hybrid (PIH (P)) which was found to inhibit ciliogenesis by inhibiting both the acetylation and polymerization of tubulin subunits. Here, we have evaluated the anticancer activities of PIH (P) and its water soluble derivatives. Three water soluble derivatives of PIH (P) namely 6 A, 6B and 6 C were synthesized. Among PIH (P) series of compounds, PIH (P) and 6 C were found to be the most potent compounds showing anti-proliferative and cytoskeletal disrupting activities against MCF-7 cells. Not only that, PIH (P) and 6 C also showed a promising effect in preventing cancer cell migration, invasion and colony-formation and helped to reduce spheroid formation by several-folds. They have potential to inhibit the activity of proteins (N-Cadherin, Vimentin) responsible for Epithelial to Mesenchymal Transition (EMT). Hence, this class of compound could be a new antimitotic agent that is different from taxol with respect to mechanism, particularly by destabilizing tubulin rather than causing stabilization.

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Current advances of tubulin inhibitors as dual acting small molecules for cancer therapy

Cited by 106 publications

References 215 publications

Antiproliferative effects on tumor cells of the synthesized gold nanoparticles against Hep2 liver cancer cell line

Antiproliferative effects on tumor cells of the synthesized gold nanoparticles against Hep2 liver cancer cell line

A Scaffold‐Diversity Synthesis of Biologically Intriguing Cyclic Sulfonamides

Evaluation of a Tubulin‐Targeted Pyrimidine Indole Hybrid Molecule as an Anticancer Agent

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