-
The Journal of Physical Chemistry. B Aug 2021The microtubule is regarded as the key target for designing anticancer and neurotherapeutic drugs due to its functional importance in eukaryotic cells including neurons....
Fluorine Substituted Proline Enhances the Tubulin Binding Potential of a Tetrapeptide at the GTP Binding Pocket Causing the Inhibition of Microtubule Motility and an Antimitotic Effect.
The microtubule is regarded as the key target for designing anticancer and neurotherapeutic drugs due to its functional importance in eukaryotic cells including neurons. The microtubule is a dynamic hollow polymer tube consisting of α,β-tubulin heterodimer. Polymerization of α,β-tubulin heterodimer resulted in microtubule formation. GTP plays a crucial role in microtubule polymerization. It binds at the exchangeable binding site of the β-tubulin heterodimer, and it is one of the most crucial therapeutic hot spots for designing anticancer therapeutics. In this manuscript, we have shown using an strategy and various and cellular experiments that the binding affinity to the tubulin and cancer therapeutic potential of an exchangeable GTP/GDP binding antimitotic tetrapeptide (SP: Ser-Leu-Arg-Pro) is increased through changing proline with the multifluorine substituted proline. This study showcases the importance of the proline amino acid and its pyrrolidine ring in the regulation of binding with tubulin at the GTP binding pocket.
Topics: Antimitotic Agents; Binding Sites; Fluorine; Guanosine Triphosphate; Microtubules; Proline; Tubulin
PubMed: 34328335
DOI: 10.1021/acs.jpcb.1c04323 -
European Journal of Medicinal Chemistry Feb 2022We recently discovered a new family of prodrugs deriving from phenyl 4-(2-oxo-3-imidazolidin-1-yl)benzenesulfonates (PIB-SOs) bioactivatable by cytochrome P450 1A1...
Branched alkyl of phenyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates as unique cytochrome P450 1A1-activated antimitotic prodrugs: Biological evaluation and mechanism of bioactivation.
We recently discovered a new family of prodrugs deriving from phenyl 4-(2-oxo-3-imidazolidin-1-yl)benzenesulfonates (PIB-SOs) bioactivatable by cytochrome P450 1A1 (CYP1A1) into potent antimitotics referred to as phenyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates (PAIB-SOs). PAIB-SOs display significant selectivity toward human breast cancer cells based on the N-dealkylation of PAIB-SOs into their corresponding PIB-SOs by CYP1A1. In this study, we have evaluated the molecular mechanism of the bioactivation of PAIB-SOs into PIB-SOs by branching the linear alkyl chain on the imidazolidin-2-one (IMZ) moiety of PAIB-SOs by branched alkyl groups such as isopropyl, isobutyl and sec-butyl. Our results show that PAIB-SOs bearing an isobutyl group on the IMZ moiety and either a methoxy, a chloro or a bromo group at positions 3, 3,5 or 3,4,5 on the aromatic ring B exhibit antiproliferative activity ranging from 0.13 to 6.9 μM and selectivity toward MCF7 and MDA-MB-468 mammary cancer cells comparatively to other cell lines tested. Moreover, the most potent and selective PAIB-SOs bearing an isobutyl group and either a 3,5-Cl (44), 3,5-Br (45) or a 3,4,5-OMe (46) on the IMZ moiety exhibit antiproliferative activity in the sub-micromolar range and high selectivity ratios toward mammary cancer cells. They stop the cell cycle of MCF7 cells in the G2/M phase and disrupt their cytoskeleton. Furthermore, our studies evidenced that PAIB-SOs bearing either an isopropyl, a sec-butyl or an isobutyl group are hydroxylated on the carbon atom adjacent to the IMZ (Cα-OH) but only PAIB-SOs bearing an isobutyl group are bioactivated into PIB-SOs. Finally, PAIB-SOs 45 and 46 exhibit low toxicity toward normal cells and chick embryos and are thus promising antimitotic prodrugs highly selective toward CYP1A1-expressing breast cancer cells.
Topics: Animals; Antimitotic Agents; Benzenesulfonates; Cell Line, Tumor; Cell Proliferation; Chick Embryo; Chickens; Cytochrome P-450 CYP1A1; Drug Screening Assays, Antitumor; Drug Stability; G2 Phase Cell Cycle Checkpoints; Half-Life; Humans; Microsomes, Liver; Microtubules; Prodrugs; Structure-Activity Relationship; Substrate Specificity
PubMed: 34839998
DOI: 10.1016/j.ejmech.2021.114003 -
Journal of Natural Products Mar 2015A new tricyclic sesquiterpene, named meleucanthin (1), was isolated from an extract of the leaves and branches of Melampodium leucanthum, along with four known...
A new tricyclic sesquiterpene, named meleucanthin (1), was isolated from an extract of the leaves and branches of Melampodium leucanthum, along with four known germacranolide sesquiterpene lactones, leucanthin-A (2), leucanthin-B (3), melampodin-A acetate (4), and 3α-hydroxyenhydrin (5). The chemical structure of 1 was elucidated by analysis of 1D and 2D NMR and mass spectrometric data. All compounds exhibited antiproliferative and cytotoxic efficacy against PC-3 and DU 145 prostate cancer cells, as well as HeLa cervical cancer cells, with IC50 values ranging from 0.18 to 9 μM. These compounds were effective in clonogenic assays and displayed high cellular persistence. They were also found to be capable of circumventing P-glycoprotein-mediated drug resistance. Mechanism of action studies showed that 4 caused an accumulation of cells in the G2/M phase of the cell cycle, and 2-5 caused the formation of abnormal mitotic spindles. These results suggest the cytotoxic effects of these germacranolides involve inhibition of mitotic spindle function, and it is likely that other mechanisms additionally contribute to cell death. These studies also demonstrate the possibility of isolating new, biologically active compounds from indigenous Texas plants.
Topics: Antimitotic Agents; Antineoplastic Agents, Phytogenic; Asteraceae; Cell Cycle; Drug Screening Assays, Antitumor; Female; HeLa Cells; Humans; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Sesquiterpenes; Texas
PubMed: 25685941
DOI: 10.1021/np500768s -
Bioorganic & Medicinal Chemistry Letters Jul 2007We report the synthesis, antiproliferative activity, and SAR of novel heterocyclic ketones derived from carbazole sulfonamides. Most of the heterocyclic ketones showed...
We report the synthesis, antiproliferative activity, and SAR of novel heterocyclic ketones derived from carbazole sulfonamides. Most of the heterocyclic ketones showed strong cytotoxicities. (N-1-Methylindole-5-yl)-(3,4,5-trimethoxyphenyl)-methanone 8b gave the most potent cytotoxicity (9.2-26 nM) against seven human tumor cell lines. The mechanism of action of the heterocyclic ketones appears to involve targeting of tubulin, similar to that of CA-4 and different from the carbazole sulfonamides.
Topics: Antimitotic Agents; Antineoplastic Agents; Carbazoles; Cell Line, Tumor; Chemistry, Pharmaceutical; Drug Design; Drug Screening Assays, Antitumor; Humans; Inhibitory Concentration 50; Ketones; Models, Chemical; Structure-Activity Relationship; Sulfonamides; Tubulin
PubMed: 17482458
DOI: 10.1016/j.bmcl.2007.04.048 -
Nature Chemistry Nov 2009Microtubules are polymeric structures formed by the self-assembly of tubulin dimers. The growth and shrinkage of these dynamic arrays have a key role during the...
Microtubules are polymeric structures formed by the self-assembly of tubulin dimers. The growth and shrinkage of these dynamic arrays have a key role during the cell-proliferation process. This makes tubulin the molecular target of many anticancer drugs currently in use or under clinical trial. Their impressive success is limited by the onset of resistant tumour cells during the treatment, so new resistance-proof molecules need to be developed. Here we use molecular dynamics and free-energy calculations to study the network of interactions that allow microtubule formation. Modelling the protein-protein interface allows us to identify the amino acids responsible for tubulin-tubulin binding and thus to design peptides, which correspond to tubulin subsequences, that interfere with microtubule formation. We show that the application of molecular modelling techniques leads to the identification of peptides that exhibit antitubulin activity both in vitro and in cultured cells.
Topics: Amino Acid Sequence; Antimitotic Agents; Cell Line, Tumor; Computational Biology; Drug Design; Humans; Microtubules; Molecular Dynamics Simulation; Oligopeptides; Protein Multimerization; Protein Structure, Quaternary; Tubulin
PubMed: 21378956
DOI: 10.1038/nchem.401 -
Environmental Technology Feb 2023In the present study, endophytic fungus, isolated from was used to analyze phytochemical studies by qualitative and GC-MS methods. The endophytic fungus yielded novel...
In the present study, endophytic fungus, isolated from was used to analyze phytochemical studies by qualitative and GC-MS methods. The endophytic fungus yielded novel compound penisimplicissin identified through GC-MS studies. Further, was conjugated with C60 fullerene nanoparticles (Ps-FNPs) were verified using UV-vis spectra, XRD, FTIR, DLS, EDX and SEM. Ps-FNPs was confirmed using UV-visible spectra with a peak at 260 nm. The IR bands were recorded at 2085, 1428, 1181, 661, 652, 644, 628, and 604 cm-1. The Ps-FNPs treated cells showed a nucleolar shrinkage and cell arrest atprophase, binuclear and multinucleolar cells, a chromosomal bridge and diversion at anaphase was observed, whereas, chromosomal fragment and abnormal distribution at metaphase stage. The Ps-FNPs exhibited a noteworthy anticancer activity on lung cancer cell line H1975 through cytotoxicity. The cytotoxicity was induced by increasing caspase-3, 7, and 9 activities and also showed highest inhibition in xanthine oxidase and COX-II assay proved good anti-inflammatory activity. Ps-FNPs have been extensively studied for photocatalytic activity test against Rhodamine B, Methylene blue and nigrosine showed potential dye degradation in the presence of sunlight proved to be novel photocatalysts. With all the results recorded, Ps-FNPs also have a synergetic effect having on anti-mitotic, anticancer, anti-inflammation potential and photocatalytic degradation of dyes. Hence, the conjugated Ps-FNPs could be one of the potent nano-drug formulations in future. Thus, the present study gives a clear idea of the multifaceted therapeutic and photocatalytic applications.
Topics: Antimitotic Agents; Photolysis; Fungi
PubMed: 34559029
DOI: 10.1080/09593330.2021.1985621 -
Angewandte Chemie (International Ed. in... Mar 2014Leiodermatolide is an antimitotic macrolide isolated from the marine sponge Leiodermatium sp. whose potentially novel tubulin-targeting mechanism of action makes it an...
Leiodermatolide is an antimitotic macrolide isolated from the marine sponge Leiodermatium sp. whose potentially novel tubulin-targeting mechanism of action makes it an exciting lead for anticancer drug discovery. In pursuit of a sustainable supply, we report a highly stereocontrolled total synthesis (3.2% yield) based on a convergent sequence of palladium-mediated fragment assembly and macrolactonization. Boron-mediated aldol reactions were used to configure the three key fragments 2, 5, and 6 by employing the appropriate enantiomer of the lactate-derived ketone 7.
Topics: Animals; Antimitotic Agents; Macrolides; Molecular Conformation; Porifera; Stereoisomerism
PubMed: 24481746
DOI: 10.1002/anie.201310164 -
Journal of Medicinal Chemistry Oct 2011A new series of resveratrol analogues was designed, synthesized, and demonstrated to be tubulin polymerization inhibitors. Most of these compounds exhibited...
A new series of resveratrol analogues was designed, synthesized, and demonstrated to be tubulin polymerization inhibitors. Most of these compounds exhibited antiproliferative activity and inhibited in vitro tubulin polymerization effectively at concentrations of 4.4-68.1 and 17-62 μM, respectively. Flow cytometry studies showed that compounds 7c, 7e, and 7g arrested cells in the G2/M phase of the cell cycle. Immunocytochemistry revealed loss of intact microtubule structure in cells treated with 7c and 7e. Docking of compounds 7c and 7e with tubulin suggested that the A-ring of the compounds occupies the colchicine binding site of tubulin, which coordinates with Cys241, Leu242, Ala250, Val318, Val328, and I378, and that the nitrovinyl side chain forms two hydrogen bonds with the main loop of the β-chain at Asn249 and Ala250.
Topics: Antimitotic Agents; Caspase 3; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Nucleus; Drug Design; Drug Screening Assays, Antitumor; Enzyme Activation; Humans; Microtubules; Models, Molecular; Nitro Compounds; Resveratrol; Stereoisomerism; Stilbenes; Structure-Activity Relationship; Tubulin Modulators; Vinyl Compounds
PubMed: 21851083
DOI: 10.1021/jm200639r -
European Journal of Medicinal Chemistry Mar 2021Three different series of cis-restricted analogues of combretastatin A-4 (CA-4), corresponding to thirty-nine molecules that contained a pyrrole nucleus interposed...
Three different series of cis-restricted analogues of combretastatin A-4 (CA-4), corresponding to thirty-nine molecules that contained a pyrrole nucleus interposed between the two aryl rings, were prepared by a palladium-mediated coupling approach and evaluated for their antiproliferative activity against six human cancer cell lines. In the two series of 1,2-diaryl pyrrole derivatives, results suggested that the presence of the 3',4',5'-trimethoxyphenyl moiety at the N-1 position of the pyrrole ring was more favorable for antiproliferative activity. In the series of 3,4-diarylpyrrole analogues, three compounds (11i-k) exhibited maximal antiproliferative activity, showing excellent antiproliferative activity against the CA-4 resistant HT-29 cells. Inhibition of tubulin polymerization of selected 1,2 pyrrole derivatives (9a, 9c, 9o and 10a) was similar to that observed with CA-4, while the isomeric 3,4-pyrrole analogues 11i-k were generally from 1.5- to 2-fold more active than CA-4. Compounds 11j and 11k were the only compounds that showed activity as inhibitors of colchicine binding comparable to that CA-4. Compound 11j had biological properties consistent with its intracellular target being tubulin. This compound was able to block the cell cycle in metaphase and to induce significant apoptosis at a concentration of 25 nM, following the mitochondrial pathway, with low toxicity for normal cells. More importantly, compound 11j exerted activity in vivo superior to that of CA-4P, being able to significantly reduce tumor growth in a syngeneic murine tumor model even at the lower dose tested (5.0 mg/kg).
Topics: Antimitotic Agents; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Colchicine; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Polymerization; Pyrroles; Structure-Activity Relationship; Tubulin; Tubulin Modulators
PubMed: 33550186
DOI: 10.1016/j.ejmech.2021.113229 -
Biochemical Pharmacology Sep 2016A series of compounds containing the sulfonamide scaffold were synthesized and screened for their in vitro anticancer activity against a representative panel of human...
A series of compounds containing the sulfonamide scaffold were synthesized and screened for their in vitro anticancer activity against a representative panel of human cancer cell lines, leading to the identification of N-(2-methyl-1H-indol-5-yl)-1-naphthalenesulfonamide (8e) as a compound showing a remarkable activity across the panel, with IC50 values in the nanomolar-to-low micromolar range. Cell cycle distribution analysis revealed that 8e promoted a severe G2/M arrest, which was followed by cellular senescence as indicated by the detection of senescence-associated β-galactosidase (SA-β-gal) in 8e-treated cells. Prolonged 8e treatment also led to the onset of apoptosis, in correlation with the detection of increased Caspase 3/7 activities. Despite increasing γ-H2A.X levels, a well-established readout for DNA double-strand breaks, in vitro DNA binding studies with 8e did not support interaction with DNA. In agreement with this, 8e failed to activate the cellular DNA damage checkpoint. Importantly, tubulin staining showed that 8e promoted a severe disorganization of microtubules and mitotic spindle formation was not detected in 8e-treated cells. Accordingly, 8e inhibited tubulin polymerization in vitro in a dose-dependent manner and was also able to robustly inhibit cancer cell motility. Docking analysis revealed a compatible interaction with the colchicine-binding site of tubulin. Remarkably, these cellular effects were reversible since disruption of treatment resulted in the reorganization of microtubules, cell cycle re-entry and loss of senescent markers. Collectively, our data suggest that this compound may be a promising new anticancer agent capable of both reducing cancer cell growth and motility.
Topics: Antimitotic Agents; Apoptosis; Cell Movement; Cell Proliferation; DNA Damage; Drug Screening Assays, Antitumor; Humans; Indoles; Jurkat Cells; MCF-7 Cells; Microtubules; Molecular Structure; Sulfonamides; Tubulin
PubMed: 27349984
DOI: 10.1016/j.bcp.2016.06.016