Synthesis and biological evaluation of 1,2,3-triazole linked aminocombretastatin conjugates as mitochondrial mediated apoptosis inducers

Kamal, Ähmed; Bajee, Shaik; Nayak, V. Lakshma; Nagaraju, Burri; Kapure, Jeevak Sopanrao; Malik, M. Shaheer; Shaik, Thokhir Basha; Prasad, B.

doi:10.1016/j.bmc.2014.08.008

Cited by 28 publications

(12 citation statements)

References 47 publications

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“…The tubulin polymerization inhibition property of these conjugates were also significant with IC 50 values of around 1.0 μM. 58 In an earlier report, Vilanova and co-workers synthesized hybrids of CA-4 and pironetin fragment by modification at ring B of CA-4. The two pharmacophoric moieties were tethered through a spacer of varying length with a triazole ring and some of the hybrids exhibited comparable cytotoxicity with that of CA-4 with lowered toxicity towards normal cells.…”

Section: Modification Of Ring Bmentioning

confidence: 92%

Recent advances in combretastatin based derivatives and prodrugs as antimitotic agents

et al. 2017

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The dynamic and crucial role of tubulin in different cellular functions rendered it a promising target in anticancer drug development. Combretastatin A-4 (CA-4), an inhibitor of tubulin polymerization isolated from natural sources, is a lead molecule with significant cytotoxicity against tumour cells. Owing to its non polar nature it exhibits low solubility in natural biological fluids, thereby prompting the development of new CA-4 based derivatives. The modification of this lead molecule was mostly carried out by keeping the crucial -orientation of the double bond intact, along with a trimethoxyphenyl aromatic ring, by employing different approaches. The issue of solubility was also addressed by the development of water soluble prodrugs of CA-4. The present review highlights the investigations into the parallel development of both new CA-4 based derivatives and prodrugs in the past few years.

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Section: Modification Of Ring Bmentioning

confidence: 92%

Recent advances in combretastatin based derivatives and prodrugs as antimitotic agents

et al. 2017

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“…The mixtures for these experiments included tubulin (3 mg mL −1 ) in PEM buffer and GTP (1 μ m ) in the presence or absence of test compounds at concentrations of 0.1, 0.5, 1, 2, and 4 μ m . Polymerization was monitored by an increase in the fluorescence, as mentioned above at 37 °C …”

Section: Methodsmentioning

confidence: 99%

“…The mixtures for these experiments included tubulin (3 mg mL À1 )i nP EM buffer and GTP (1 mm)i nt he presence or absence of test compounds at concentrations of 0.1, 0.5, 1, 2, and 4 mm.P olymerization was monitored by an increase in the fluorescence, as mentioned above at 37 8C. [48] Colchicine competition assay:T est compounds 7a and 9a at concentrations of 0.1, 0.5, 1, 5, and 10 mm were incubated with 3 mm tubulin in the presence and absence of 3 mm colchicine in 30 mm Tris buffer for 60 min at 37 8C. CA-4 was used as ap ositive control, whereas paclitaxel, which binds at the taxane site, was used as an egative control.…”

Section: Biological Methodsmentioning

confidence: 99%

Design, Synthesis, and in vitro and in vivo Evaluations of (Z)‐3,4,5‐Trimethoxystyrylbenzenesulfonamides/sulfonates as Highly Potent Tubulin Polymerization Inhibitors

et al. 2017

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Newer therapeutics can be developed in drug discovery by adopting the strategy of scaffold hopping of the privileged scaffolds from known bioactive compounds. This strategy has been widely employed in drug-discovery processes. Structure-based docking studies illustrate the basic underlying concepts and reveal that interactions of the sulfonamide group and hydrophobic interactions are crucial. On the basis of this strategy, over 60 synthetic analogues were synthesized and evaluated for their cytotoxicity against the NCI panel of 60 human cancer cell lines; the majority of these compounds exhibited promising cytotoxicity with GI values ranging between 18 and 50 nm. Among these compounds, (Z)-N-[2,3-dimethoxy-5-(3,4,5-trimethoxystyryl)phenyl]-4-methoxybenzenesulfonamide (7 a) and (Z)-N-[2-hydroxy-3-methoxy-6-(3,4,5-trimethoxystyryl)phenyl]-4-methoxybenzenesulfonamide (9 a) were found to be potent. Similar results were obtained against three human cancer cell lines with IC values ranging between 0.04 and 3.0 μm. Studies aimed at elucidating the mechanism of action of these new analogues revealed that they inhibited the in vitro polymerization of tubulin and disorganized the assembly of microtubules in HeLa and MCF-7cancer cells. Lead compounds 7 a and 9 a displayed notable in vivo antitumor activity in a HeLa tumor xenograft model. Our studies have resulted in the identification of a scaffold that can target tubulin polymerization, which should have significant potential toward the development of new antitumor drugs.

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“…Combretastatin A-4 disodium phosphate (CA4DP, see Figure 1) is a water-soluble prodrug of CA-4 that shows potent antivascular and antitumor effects in a wide variety of tumor cell lines [8]. 3 -Aminocombretastatin (AmCA-4, see Figure 1) is a non-natural combretastatin analogue that also shows strong cytotoxicity, inhibition of tubulin polymerization and antivascular activity [9][10][11].…”

Section: Figurementioning

confidence: 99%

Synthesis of Combretastatin A-4 and 3′-Aminocombretastatin A-4 derivatives with Aminoacid Containing Pendants and Study of their Interaction with Tubulin and as Downregulators of the VEGF, hTERT and c-Myc Gene Expression

et al. 2020

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Natural product combretastatin A-4 (CA-4) and its nitrogenated analogue 3′-aminocombretastatin A-4 (AmCA-4) have shown promising antitumor activities. In this study, a range of CA-4 and AmCA-4 derivatives containing amino acid pendants have been synthesized in order to compare their biological actions with those of their parent compounds. Thus, inhibition of cell proliferation on tumor cell lines HT-29, MCF-7 and A-549, as well as on the nontumor cell line HEK-273; in vitro tubulin polymerization; mitotic cell arrest; action on the microtubule cell network and inhibition of VEGF, hTERT, and c-Myc genes have been evaluated. Some AmCA-4 derivatives bearing L-amino acids exhibited inhibition of cell proliferation at low nanomolar levels exceeding the values shown by AmCA-4. Furthermore, while CA-4 and AmCA-4 derivatives do not show significant effects on the in vitro tubulin polymerization and cell cycle arrest, some selected CA-4 and AmCA-4 derivatives are able to cause total depolymerization of the microtubule network on A-549 cells. The best results were obtained in the inhibition of gene expression, particularly on the VEGF gene, in which some AmCA-4 derivatives greatly exceeded the inhibition values achieved by the parent compound.

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Synthesis and biological evaluation of 1,2,3-triazole linked aminocombretastatin conjugates as mitochondrial mediated apoptosis inducers

Cited by 28 publications

References 47 publications

Recent advances in combretastatin based derivatives and prodrugs as antimitotic agents

Recent advances in combretastatin based derivatives and prodrugs as antimitotic agents

Design, Synthesis, and in vitro and in vivo Evaluations of (Z)‐3,4,5‐Trimethoxystyrylbenzenesulfonamides/sulfonates as Highly Potent Tubulin Polymerization Inhibitors

Synthesis of Combretastatin A-4 and 3′-Aminocombretastatin A-4 derivatives with Aminoacid Containing Pendants and Study of their Interaction with Tubulin and as Downregulators of the VEGF, hTERT and c-Myc Gene Expression

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