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Molecules (Basel, Switzerland) Mar 2019This work presents an account of the reactivity behavior of the anticancer marine drugs, Soblidotin and Tasidotin, based on the calculation of the global and local...
This work presents an account of the reactivity behavior of the anticancer marine drugs, Soblidotin and Tasidotin, based on the calculation of the global and local descriptors resulting from Chemical Reactivity Theory (CRT), also known as Conceptual DFT, for their consideration as a useful complement to approximations based on Molecular Docking. The information on the global and local reactivity descriptors of the Soblidotin and Tasidotin molecules, obtained through our proposed methodology, may be used for the design of new pharmaceutical analogs by relying on the chemical interactions between these peptides and their protein-type biological receptors. It can be concluded that the CRT approximation to the global and local chemical reactivity, based on the descriptors, can provide interesting information for the consideration of both molecules as potential therapeutic drugs. This is complemented by a study on Advanced Glycation Endproduct (AGE) inhibition, by comparison with the usual molecular systems considered for the task, as a re-purposing study. Finally, the bioactivity scores for Soblidotin and Tasidotin are predicted through an empirical procedure, based on comparison with molecular structures with well-known pharmacological properties.
Topics: Antimicrobial Cationic Peptides; Antineoplastic Agents; Aquatic Organisms; Glycation End Products, Advanced; Models, Molecular; Molecular Conformation; Peptides; Structure-Activity Relationship
PubMed: 30901820
DOI: 10.3390/molecules24061115 -
Analytical Cellular Pathology... 2015Microtubules are dynamic and structural cellular components involved in several cell functions, including cell shape, motility, and intracellular trafficking. In... (Review)
Review
Microtubules are dynamic and structural cellular components involved in several cell functions, including cell shape, motility, and intracellular trafficking. In proliferating cells, they are essential components in the division process through the formation of the mitotic spindle. As a result of these functions, tubulin and microtubules are targets for anticancer agents. Microtubule-targeting agents can be divided into two groups: microtubule-stabilizing, and microtubule-destabilizing agents. The former bind to the tubulin polymer and stabilize microtubules, while the latter bind to the tubulin dimers and destabilize microtubules. Alteration of tubulin-microtubule equilibrium determines the disruption of the mitotic spindle, halting the cell cycle at the metaphase-anaphase transition and, eventually, resulting in cell death. Clinical application of earlier microtubule inhibitors, however, unfortunately showed several limits, such as neurological and bone marrow toxicity and the emergence of drug-resistant tumor cells. Here we review several natural and synthetic microtubule-targeting agents, which showed antitumor activity and increased efficacy in comparison to traditional drugs in various preclinical and clinical studies. Cryptophycins, combretastatins, ombrabulin, soblidotin, D-24851, epothilones and discodermolide were used in clinical trials. Some of them showed antiangiogenic and antivascular activity and others showed the ability to overcome multidrug resistance, supporting their possible use in chemotherapy.
Topics: Antineoplastic Agents; Humans; Microtubules; Neoplasms
PubMed: 26484003
DOI: 10.1155/2015/690916 -
British Journal of Cancer Apr 2007Growth of human tumours depends on the supply of oxygen and nutrients via the surrounding vasculature. Therefore tumour vasculature is an attractive target for... (Review)
Review
Growth of human tumours depends on the supply of oxygen and nutrients via the surrounding vasculature. Therefore tumour vasculature is an attractive target for anticancer therapy. Apart from angiogenesis inhibitors that compromise the formation of new blood vessels, a second class of specific anticancer drugs has been developed. These so-called vascular disrupting agents (VDAs) target the established tumour vasculature and cause an acute and pronounced shutdown of blood vessels resulting in an almost complete stop of blood flow, ultimately leading to selective tumour necrosis. As a number of VDAs are now being tested in clinical studies, we will discuss their mechanism of action and the results obtained in preclinical studies. Also data from clinical studies will be reviewed and some considerations with regard to the future development are given.
Topics: Animals; Antineoplastic Agents; Blood Vessels; Humans; Neoplasms; Neovascularization, Pathologic; Oligopeptides; Organophosphorus Compounds; Regional Blood Flow; Stilbenes; Tubulin Modulators; Xanthones
PubMed: 17375046
DOI: 10.1038/sj.bjc.6603694 -
Computers in Biology and Medicine Aug 2021Coronavirus disease 2019 (COVID-19) is an ongoing pandemic. The virus that causes the disease, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2),...
Coronavirus disease 2019 (COVID-19) is an ongoing pandemic. The virus that causes the disease, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), predominantly infects the respiratory tract, which may lead to pneumonia and death in severe cases. Many marine compounds have been found to have immense medicinal value and have gained approval from the Food and Drug Administration (FDA), and some are being tested in clinical trials. In the current investigation, we redirected a number of marine compounds toward SARS-CoV-2 by targeting the main protease (M, PDB ID: 6Y2F), subjecting them to several advanced computational techniques using co-crystallised ligand as the reference compound. The results of the binding affinity studies showed that two compounds, eribulin mesylate (eri) and soblidotin (sob), displayed higher docking scores than did the reference compound. When these compounds were assessed using molecular dynamics simulation, it was evident that they demonstrated stable binding at the binding pocket of the target protein. The systems demonstrated stable root mean square deviation and radius of gyration values, while occupying the binding pocket during the simulation run. Furthermore, the essential dynamics and free energy landscape exploration revealed that the protein had navigated through a minimal energy basin and demonstrated favourable conformation while binding to the proposed inhibitors. Collectively, our findings suggest that two marine compounds, namely eri and sob, show potential as SARS-CoV-2 main protease inhibitors.
Topics: Antiviral Agents; Aquatic Organisms; Biological Products; Coronavirus 3C Proteases; Molecular Docking Simulation; Molecular Dynamics Simulation; Pandemics; Protease Inhibitors; SARS-CoV-2
PubMed: 34252682
DOI: 10.1016/j.compbiomed.2021.104525 -
Anticancer Research 2006TZT-1027 (Soblidotin), a newly synthesized dolastatin 10 derivative that depolymerizes microtubules, has potent antitumor activity.
BACKGROUND
TZT-1027 (Soblidotin), a newly synthesized dolastatin 10 derivative that depolymerizes microtubules, has potent antitumor activity.
MATERIALS AND METHODS
Cell-killing kinetic analysis was performed by the colony-forming assay and the kinetics of TZT-1027 were compared with those of neocarzinostatin, adriamycin and vincristine, known to be typical concentration-, AUC- and time-dependent agents, respectively. DNA fragmentation was detectable by electrophoresis, cytotoxicity was evaluated by MTT assay and antitumor activity was examined by measuring the tumor weight after treatment.
RESULTS
TZT-1027 exhibited its cytocidal and apoptosis-inducing activity in a time-dependent manner. Its growth-inhibitory effect was less affected by overexpression of P-glycoprotein than that of other tubulin inhibitors and was not affected by the overexpression of breast cancer resistance protein or multidrug resistance-associated protein. TZT-1027 exhibited potent antitumor activities in an in vivo tumor model in which vincristine and docetaxel failed to show effectiveness.
CONCLUSION
Because its growth-inhibitory and antitumor activities were superior to those of the other drugs tested, including the tubulin inhibitors paclitaxel, docetaxel and vincristine, TZT-1027 should be useful in the chemotherapy of tumors that are not responsive to other tubulin inhibitors.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Animals; Antineoplastic Agents; Cell Death; Cell Growth Processes; Cell Line, Tumor; Colonic Neoplasms; DNA Fragmentation; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Fibrosarcoma; Humans; Male; Mice; Mice, Inbred BALB C; Multidrug Resistance-Associated Proteins; Neoplasm Proteins; Oligopeptides; Xenograft Model Antitumor Assays
PubMed: 16827132
DOI: No ID Found -
Frontiers in Molecular Biosciences 2020Although it is known crocin, a hydrophilic compound from the herbal plant L., has promising antitumor activity, the detailed mechanism of its antitumor activity was not...
Although it is known crocin, a hydrophilic compound from the herbal plant L., has promising antitumor activity, the detailed mechanism of its antitumor activity was not well understood. Recent experiments suggested tubulin as the primary target for the antitumor activity of crocin. However, due to a lack of crystal structure of tubulin bound with crocin, the exact binding mode and interaction between crocin and tubulin remains exclusive. In the present work, a computational study by integrating multiple conformation docking, molecular dynamics simulation as well as residue interaction network analysis was performed to investigate the molecular mechanism of crocin-tubulin interaction. By comparing the docking score, the most likely binding mode CRO_E1 were identified from 20 different binding modes of crocin in the vinca binding pockets. Further molecular dynamics simulation of CRO_E1 complex showed the binding of crocin is more stable than the inhibitor soblidotin and vinblastine. During the simulation course, an excessive number of hydrogen bonds were observed for the ligand crocin. The binding free energy of crocin-tubulin complex was calculated as -79.25 ± 7.24 kcal/mol, which is almost twice of the ligand soblidotin and vinblastine. By using energy decomposition, hot residues for CRO_E1 were identified as Gln, Gln, Thr, Ser, Pro-Lys-Val-Ser-Asp, Tyr, and Asn in the β-chain, and Asp, Ala-Leu, Val, Asn, and Ile in the α-chain. Residue interaction network analysis also showed the importance of these hot residues in the interaction network of crocin-tubulin complex. In addition, a common residue motif Val-Xxx-Asp was discovered for all three bindings, suggesting its importance in future drug design. The study could provide valuable insights into the interaction between crocin and tubulin, and give suggestive clues for further experimental studies.
PubMed: 33251248
DOI: 10.3389/fmolb.2020.586970 -
Anticancer Research 2006TZT-1027 (Soblidotin), an antimicrotubule drug, has shown potent antitumor efficacy in various antitumor models, and has entered into phase I clinical trials. To...
BACKGROUND
TZT-1027 (Soblidotin), an antimicrotubule drug, has shown potent antitumor efficacy in various antitumor models, and has entered into phase I clinical trials. To determine those anticancer drugs to be combined with TZT-1027 in clinical trials, the combination effects of TZT-1027 with other anticancer drugs were examined.
MATERIALS AND METHODS
Two in vivo antitumor models, the murine P388 leukemia ascites tumor model and the human non-small cell lung cancer A549 solid tumor model, were used and cisplatin (CDDP), gemcitabine (GEM), irinotecan hydrochloride (CPT-11), fluorouracil (5-FU), paclitaxel (PTX) and docetaxel (DTX) were selected to be combined with TZT-1027. Regarding the schedule of combination administration, simultaneous administration and sequential administration (TZT-1027 first and combined drugs administered 24 h later, and vice versa) were employed.
RESULTS
A significant increase in lifespan was observed when TZT-1027 was combined with CDDP, GEM and CPT-11 in the P388 cell ascites tumor model, and a significant inhibition of growth was observed when TZT-1027 was combined with CDDP, GEM and DTX in the A549 solid tumor model. Sequential administration, particularly when the combined drug was administered first, showed the most potent antitumor efficacy.
CONCLUSION
These findings strongly suggest that a significant combination effect of TZT-1027 and these antitumor drugs can be expected in clinical trials for solid tumors.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma, Non-Small-Cell Lung; Cisplatin; Deoxycytidine; Docetaxel; Drug Administration Schedule; Drug Screening Assays, Antitumor; Female; Fluorouracil; Humans; Irinotecan; Leukemia P388; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Oligopeptides; Paclitaxel; Taxoids; Gemcitabine
PubMed: 16619516
DOI: No ID Found -
Cancer Science Sep 2003TZT-1027 (Soblidotin), an antimicrotubule agent, has been demonstrated to show potent antitumor effects, though the relationships among antitumor effect, cytotoxicity...
TZT-1027 (Soblidotin), an antimicrotubule agent, has been demonstrated to show potent antitumor effects, though the relationships among antitumor effect, cytotoxicity and anti-vascular effect of TZT-1027 have not been studied. We established in vivo human lung vascular-rich tumor models using a vascular endothelial growth factor-secreting tumor (SBC-3/VEGF). SBC-3/VEGF tumors exhibited a high degree of angiogenesis in comparison with the mock transfectant (SBC-3/Neo) tumors in a dorsal skinfold chamber model and grew much faster and larger than SBC-3/Neo tumors in the tumor growth study. The antitumor activity of antimicrotubule agents, including TZT-1027, was evaluated in both early- and advanced-stage SBC-3/Neo and SBC-3/VEGF tumor models to elucidate the relationship between the antitumor activity and anti-vascular effect of these agents. TZT-1027 exhibited potent antitumor activity against both early- and advanced-stage SBC-3/Neo and SBC-3/VEGF tumors, whereas combretastatin A4 phosphate did not. Vincristine and docetaxel exhibited potent antitumor activity against early-stage SBC-3/Neo and SBC-3/VEGF tumors, and advanced-stage SBC-3/Neo tumors, but did not exhibit activity against advanced-stage SBC-3/VEGF tumors. The difference in antitumor activity between these agents could be ascribed to differences in direct cytotoxicity and anti-vascular effect. Furthermore, a prominent accumulation of erythrocytes in the tumor vasculature, followed by leakage and scattering of these erythrocytes from the tumor vasculature, was observed after TZT-1027 administration to mice bearing advanced-stage SBC-3/VEGF tumors. These findings strongly suggest that TZT-1027 has a potent anti-vascular effect, in addition to direct cytotoxicity.
Topics: Animals; Antineoplastic Agents; Carcinoma, Small Cell; Cell Survival; Docetaxel; Erythrocytes; Female; Gene Expression Regulation, Neoplastic; Humans; Leukemia P388; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms, Experimental; Neovascularization, Pathologic; Oligopeptides; Skin; Stilbenes; Taxoids; Transfection; Vascular Endothelial Growth Factor A; Vincristine
PubMed: 12967483
DOI: 10.1111/j.1349-7006.2003.tb01526.x -
Marine Drugs Apr 2016A conformational restriction strategy was used to design and synthesize nine TZT-1027 analogues. 3-Aryl-azetidine moiety was used to replace phenylethyl group of...
A conformational restriction strategy was used to design and synthesize nine TZT-1027 analogues. 3-Aryl-azetidine moiety was used to replace phenylethyl group of TZT-1027 at the C-terminus. These analogues exhibited moderate to excellent antiproliferative activities, and the most potent compound 1a showed IC50 values of 2.2 nM against A549 and 2.1 nM against HCT116 cell lines, respectively. However, 1a could not achieve effective inhibition at all the dose levels in the A549 xenograft model (up to 5 mg/kg, injection, once a day), which is only 16%-35% inhibition at the end of the experiment.
Topics: A549 Cells; Animals; Antineoplastic Agents; Azetidines; Cell Line, Tumor; Cell Proliferation; Female; HCT116 Cells; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Oligopeptides
PubMed: 27136567
DOI: 10.3390/md14050085 -
Anticancer Research 2007TZT-1027 (Soblidotin), a microtubule (MT)-depolymerizing agent, has antivascular activity through the disruption of microtubules in vascular endothelial cells. Our aim...
BACKGROUND
TZT-1027 (Soblidotin), a microtubule (MT)-depolymerizing agent, has antivascular activity through the disruption of microtubules in vascular endothelial cells. Our aim was to elucidate the mechanism of TZT-1027-induced antivascular activity by investigating the impact of various inhibitors.
MATERIALS AND METHODS
The inhibitory effects on TZT-1027-induced antivascular activity were evaluated by a tumor perfusion study in mice bearing Colon26 tumors and a vascular permeability study on human umbilical vein endothelial cells monolayer. Western blotting analyses were performed to verify the mechanism of antivascular activity.
RESULTS
Pretreatment with docetaxel and SB220025, a p38 mitogen-activated protein kinase (MAPK) inhibitor, significantly suppressed the TZT-1027-induced reduction of tumor perfusion and increase in vascular permeability. Gross findings showed that SB220025 visibly attenuated the TZT-1027-induced widespread hemorrhage in tumors. Western blotting analyses revealed that TZT-1027 induced the phosphorylation of p38 MAPK only slightly compared to hydrogen peroxide, and that docetaxel and SB220025 increased the acetylation of alpha-tubulin an effect opposite to that of TZT-1027.
CONCLUSION
TZT-1027-induced antivascular activity was abolished by docetaxel through the stabilization of microtubules, and by p38 MAPK inhibitor not only through the regulation of the p38 MAPK pathway, but also through the direct stabilization of microtubules, similar to docetaxel.
Topics: Adenocarcinoma; Animals; Blotting, Western; Capillary Permeability; Colonic Neoplasms; Docetaxel; Drug Interactions; Endothelial Cells; Female; Humans; Imidazoles; Mice; Mice, Inbred BALB C; Oligopeptides; Phosphorylation; Protein Kinase Inhibitors; Pyrimidines; Taxoids; p38 Mitogen-Activated Protein Kinases
PubMed: 18225550
DOI: No ID Found