Taxol Analogues Research Articles

Myricetin: a potential plant-derived anticancer bioactive compound-an updated overview.

The globe is currently confronting a global fight against the deadliest cancer sickness. Chemotherapy, hormonal therapy, surgery, and radiation therapy are among cancer treatment options. Still, these treatments can induce patient side effects, including recurrence, multidrug resistance, fever, and weakness. As a result, the scientific community is always working on natural phytochemical substances. Numerous phytochemical compounds, including taxol analogues, vinca alkaloids such as vincristine and vinblastine, and podophyllotoxin analogues, are currently undergoing testing and have shown promising results against a number of the deadliest diseases, as well as considerable advantages due to their safety and low cost. According to research, secondary plant metabolites such as myricetin, a flavonoid in berries, herbs, and walnuts, have emerged as valuable bio-agents for cancer prevention. Myricetin and its derivatives have antiinflammatory, anticancer, apoptosis-inducing, and anticarcinogenic properties and can prevent cancer cell proliferation. Multiple studies have found that myricetin has anticancer characteristics in various malignancies, including colon, breast, prostate, bladder, and pancreatic cancers. Current knowledge of the anticancer effects of myricetin reveals its promise as a potentially bioactive chemical produced from plants for the prevention and treatment of cancer. This review aimed to study the numerous bioactivities, mode of action, and modification of several cellular processes that myricetin possesses to impede the spread of cancer cells. This review also addresses the challenges and future prospects of using myricetin as a anticancer drug.

"Preclinical Research to Clinical Practice: A Review of Phytochemicals in Cancer Treatment"

Cancer is a serious health issue that remains a top cause of mortality across the globe. Anticancer medications have been developed as we have understood the molecular mechanism that leads to cancer genesis has grown. Chemically produced medications, on the other hand, have had little impact on overall survival rates during the last several decades. As a result, to improve the efficacy of conventional therapies of cancer, new approaches and revolutionary chemoprevention drugs are necessary. Phytochemicals are those molecules that occur naturally in plants, are important resources for developing new medicines and may also be used to treat cancer. Only a few example include taxol analogues, vinca alkaloids such as vinblastine vincristine and, and podophyllotoxin analogues. These phytochemical generally work by interfering with molecular pathways connected to cancer formation and progress. Some of the distinct approaches include increased antioxidants status, carcinogen inactivation, reducing its rapid growth, promotion of cell cycle arrest and death, and immune system regulation. The main goal of this study is to summarise what we now know about natural product active chemicals, including their pharmacology and molecular or particular targets. The most recent advancements and limitations in the development of phytochemical-based anticancer therapies are also discussed. The author wants to boost phytochemicals research not just for its scientific worth, but also for its medicine development potential. As a result, anticancer phytochemicals that have been studied in preclinical and clinical settings have gotten a lot of attention.

High-resolution X-ray structure of three microtubule-stabilizing agents in complex with tubulin provide a rationale for drug design

Microtubule is a key component of cytoskeleton and has been considered as an important target for the treatment of cancer. In particular, the tubulin taxane-site inhibitors such as taxol analogs and epothilones have achieved great success in clinical trials. However, the structural basis of many taxane-site inhibitors is still lacking in exploring their mechanism of action. We here reported crystal complex structures for three taxane-site inhibitors, Ixabepilone, Epothilone B, and Epothilone D, which were determined to 2.4 Å, 2.4 Å, and 2.85 Å, respectively. The crystal structures revealed that these taxane-site inhibitors possess similar binding modes to that of Epothilone A at the taxane site, e.g. making critical hydrogen-bonding interactions with multiple residues on the M-loop, which facilitating the tubulin polymerization. Furthermore, we summarized the binding modes of almost all taxane-site inhibitors and identified novel taxane-site ligands with simpler chemical structures through virtual screening. On this basis, new derivatives with higher binding affinity to tubulin were designed and developed, which can form additional hydrogen bond interactions with tubulin. Overall, this work determined the mechanism of action of epothilones and provided a structural basis to design reasonably novel taxane-site inhibitors with simpler structure and improved pharmacokinetic properties.

Management of Glioblastoma Multiforme by Phytochemicals: Applications of Nanoparticle-Based Targeted Drug Delivery System.

The Glioblastoma Multiforme (GBM; grade IV astrocytoma) exhorts tumors of star-shaped glial cells in the brain. It is a fast-growing tumor that spreads to nearby brain regions specifically to cerebral hemispheres in frontal and temporal lobes. The etiology of GBM is unknown, but major risk factors are genetic disorders like neurofibromatosis and schwannomatosis, which develop the tumor in the nervous system. The management of GBM with chemo-radiotherapy leads to resistance, and current drug regimen like Temozolomide (TMZ) is less efficacious. The reasons behind the failure of drugs are due to DNA alkylation in the cell cycle by enzyme DNA guanidase and mitochondrial dysfunction. Naturally occurring bioactive compounds from plants referred as phytochemicals, serve as vital sources for anti-cancer drugs. Some prototypical examples include taxol analogs, vinca alkaloids (vincristine, vinblastine), podophyllotoxin analogs, camptothecin, curcumin, aloe-emodin, quercetin, berberine etc. These phytochemicals often regulate diverse molecular pathways, which are implicated in the growth and progression of cancers. However, the challenges posed by the presence of BBB/BBTB to restrict the passage of these phytochemicals, culminates in their low bioavailability and relative toxicity. In this review, we integrated nanotech as a novel drug delivery system to deliver phytochemicals from traditional medicine to the specific site within the brain for the management of GBM.

Phytochemicals in Cancer Treatment: From Preclinical Studies to Clinical Practice.

Cancer is a severe health problem that continues to be a leading cause of death worldwide. Increasing knowledge of the molecular mechanisms underlying cancer progression has led to the development of a vast number of anticancer drugs. However, the use of chemically synthesized drugs has not significantly improved the overall survival rate over the past few decades. As a result, new strategies and novel chemoprevention agents are needed to complement current cancer therapies to improve efficiency. Naturally occurring compounds from plants known as phytochemicals, serve as vital resources for novel drugs and are also sources for cancer therapy. Some typical examples include taxol analogs, vinca alkaloids such as vincristine, vinblastine, and podophyllotoxin analogs. These phytochemicals often act via regulating molecular pathways which are implicated in growth and progression of cancer. The specific mechanisms include increasing antioxidant status, carcinogen inactivation, inhibiting proliferation, induction of cell cycle arrest and apoptosis; and regulation of the immune system. The primary objective of this review is to describe what we know to date of the active compounds in the natural products, along with their pharmacologic action and molecular or specific targets. Recent trends and gaps in phytochemical based anticancer drug discovery are also explored. The authors wish to expand the phytochemical research area not only for their scientific soundness but also for their potential druggability. Hence, the emphasis is given to information about anticancer phytochemicals which are evaluated at preclinical and clinical level.

Taxol Analogues Exhibit Differential Effects on Photoaffinity Labeling of β-Tubulin and the Multidrug Resistance Associated P-Glycoprotein.

Several next-generation taxanes have been reported to possess high potency against Taxol-resistant cancer cell lines overexpressing βIII-tubulin and/or P-glycoprotein (P-gp), both of which are involved in drug resistance. Using a photoaffinity Taxol analogue, 2-( m-azidobenzoyl)taxol, two potent next-generation taxanes, SB-T-1214 and SB-CST-10202, exhibited distinct inhibitory effects on photolabeling of β-tubulin from different eukaryotic sources that differ in β-tubulin isotype composition. They also specifically inhibited photolabeling of P-gp, and the inhibitory effect correlated well with the steady-state accumulation of [3H]vinblastine in a multidrug resistant (MDR) cell line, SKVLB1. Several microtubule-stabilizing agents (MSAs)-resistant cell lines from the human ovarian cancer cell line Hey were isolated, and their MDR1 and βIII-tubulin levels determined. Distinct potencies of the two taxanes against different MSA-resistant cells expressing unique levels of MDR1 and βIII-tubulin were found. Cytotoxicity assays, done in the presence of verapamil, indicated that SB-T-1214 is a substrate, although not as good as Taxol, for P-gp. The mechanisms involved in drug resistance are multifactorial, and the effectiveness of new Taxol analogues depends on the interaction between the drugs and all possible targets; in this case the two major cellular targets are β-tubulin and P-gp.

Taxol®: The First Microtubule Stabilizing Agent.

Taxol®, an antitumor drug with significant activity, is the first microtubule stabilizing agent described in the literature. This short review of the mechanism of action of Taxol® emphasizes the research done in the Horwitz’ laboratory. It discusses the contribution of photoaffinity labeled analogues of Taxol® toward our understanding of the binding site of the drug on the microtubule. The importance of hydrogen/deuterium exchange experiments to further our insights into the stabilization of microtubules by Taxol® is addressed. The development of drug resistance, a major problem that arises in the clinic, is discussed. Studies describing differential drug binding to distinct β-tubulin isotypes are presented. Looking forward, it is suggested that the β-tubulin isotype content of a tumor may influence its responses to Taxol®.

2-(m-Azidobenzoyl)taxol binds differentially to distinct β-tubulin isotypes

There are seven β-tubulin isotypes present in distinct quantities in mammalian cells of different origin. Altered expression of β-tubulin isotypes has been reported in cancer cell lines resistant to microtubule stabilizing agents (MSAs) and in human tumors resistant to Taxol. To study the relative binding affinities of MSAs, tubulin from different sources, with distinct β-tubulin isotype content, were specifically photolabeled with a tritium-labeled Taxol analog, 2-(m-azidobenzoyl)taxol, alone or in the presence of MSAs. The inhibitory effects elicited by these MSAs on photolabeling were distinct for β-tubulin from different sources. To determine the exact amount of drug that binds to different β-tubulin isotypes, bovine brain tubulin was photolabeled and the isotypes resolved by high-resolution isoelectrofocusing. All bands were analyzed by mass spectrometry following cyanogen bromide digestion, and the identity and relative quantity of each β-tubulin isotype determined. It was found that compared with other β-tubulin isotypes, βIII-tubulin bound the least amount of 2-(m-azidobenzoyl)taxol. Analysis of the sequences of β-tubulin near the Taxol binding site indicated that, in addition to the M-loop that is known to be involved in drug binding, the leucine cluster region of βIII-tubulin contains a unique residue, alanine, at 218, compared with other isotypes that contain threonine. Molecular dynamic simulations indicated that the frequency of Taxol-accommodating conformations decreased dramatically in the T218A variant, compared with other β-tubulins. Our results indicate that the difference in residue 218 in βIII-tubulin may be responsible for inhibition of drug binding to this isotype, which could influence downstream cellular events.

Abstract 4496: Differential inhibition by microtubule stabilizing agents of 2-(m-azidobenzoyl)Taxol photoaffinity labeling of tubulins from different eukaryotic sources.

Abstract Distinct α- and β-tubulin isotypes are present in different quantities in diverse eukaryotic cells. The tritium-labeled photoaffinity Taxol analog, 2-(m-azidobenzoyl)Taxol, was used to photolabel tubulins prepared from HeLa cells, bovine brain and chicken erythrocytes. A 5-fold molar excess of unlabeled compound inhibited the photolabeling of tubulin by >90%, demonstrating the specificity of this photolabeling. Tubulin isotype content varies from one source to another, particularly for chicken erythrocytes that contain only one α-tubulin and one β-tubulin (α1 and βVI). 2-(m-azidobenzoyl)Taxol photoaffinity labeling of tubulin was carried out in the presence of six different microtubule stabilizing agents, including Taxol, epothilone B, discodermolide, ixabepilone, laulimalide and peloruside A. The inhibitory effects elicited by Taxol, epothilone B, discodermolide and ixabepilone, at a 5-fold molar excess, on photolabeling are different for tubulins prepared from different sources. Taxol had a minimal inhibitory effect on HeLa and bovine brain tubulin, but a strong inhibitory effect on chicken erythrocyte tubulin. Discodermolide exhibited opposite effects on photolabeling, compared to those of Taxol. This is most likely due to the presence of distinct tubulin isotypes in different sources. However, laulimalide and peloruside A that are known to bind to a different site than Taxol in β-tubulin, stimulated photolabeling of tubulins from all three sources. Stathmin (S) plays an important role in the regulation of microtubule dynamics through sequestering tubulin (T) into a T2S complex. When stathmin was incubated, in the presence of 1 mM CaCl2, with chicken erythrocyte tubulin at a tubulin:stathmin ratio of 2:1, followed by incubation with tritium-labeled 2-(m-azidobenzoyl)Taxol in a buffer containing EGTA, photolabeling of β-tubulin was markedly reduced, suggesting that stathmin inhibited binding of Taxol to tubulin. Radiolabeled photoaffinity drug analogs are useful tools for determining drug binding affinities for the different tubulin isotypes. We are currently analyzing binding affinities of 2-(m-azidobenzoyl)Taxol to different bovine brain tubulin isotypes resolved by isoelectrofocusing. Citation Format: Chia-Ping H. Yang, Hui Xiao, Susan Band Horwitz. Differential inhibition by microtubule stabilizing agents of 2-(m-azidobenzoyl)Taxol photoaffinity labeling of tubulins from different eukaryotic sources. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4496. doi:10.1158/1538-7445.AM2013-4496

Design and synthesis of simplified taxol analogs based on the T-Taxol bioactive conformation

A series of compounds designed to adopt a conformation similar to the tubulin-binding T-Taxol conformation of the anticancer drug paclitaxel has been synthesized. Both the internally bridged analogs 37–39, 41 and the open-chain analogs 27–29 and 43 were prepared. The bridged analogs 37–39 and 41 were synthesized by Grubbs’ metatheses of compounds 30–32 and 33, which, in turn, were prepared by coupling β-lactams 24–26 with alcohols 22 and 23. Both the bridged and the open-chain analogs showed moderate to good cytotoxicity.

Biomedical Applications of Tetrazine Cycloadditions

Disease mechanisms are increasingly being resolved at the molecular level. Biomedical success at this scale creates synthetic opportunities for combining specifically designed orthogonal reactions in applications such as imaging, diagnostics, and therapy. For practical reasons, it would be helpful if bioorthogonal coupling reactions proceeded with extremely rapid kinetics (k > 10(3) M(-1) s(-1)) and high specificity. Improving kinetics would minimize both the time and amount of labeling agent required to maintain high coupling yields. In this Account, we discuss our recent efforts to design extremely rapid bioorthogonal coupling reactions between tetrazines and strained alkenes. These selective reactions were first used to covalently couple conjugated tetrazine near-infrared-emitting fluorophores to dienophile-modifed extracellular proteins on living cancer cells. Confocal fluorescence microscopy demonstrated efficient and selective labeling, and control experiments showed minimal background fluorescence. Multistep techniques were optimized to work with nanomolar concentrations of labeling agent over a time scale of minutes: the result was successful real-time imaging of covalent modification. We subsequently discovered fluorogenic probes that increase in fluorescence intensity after the chemical reaction, leading to an improved signal-to-background ratio. Fluorogenic probes were used for intracellular imaging of dienophiles. We further developed strategies to react and image chemotherapeutics, such as trans-cyclooctene taxol analogues, inside living cells. Because the coupling partners are small molecules (<300 Da), they offer unique steric advantages in multistep amplification. We also describe recent success in using tetrazine reactions to label biomarkers on cells with magneto-fluorescent nanoparticles. Two-step protocols that use bioorthogonal chemistry can significantly amplify signals over both one-step labeling procedures as well as two-step procedures that use more sterically hindered biotin-avidin interactions. Nanoparticles can be detected with fluorescence or magnetic resonance techniques. These strategies are now being routinely used on clinical samples for biomarker profiling to predict malignancy and patient outcome. Finally, we discuss recent results with tetrazine reactions used for in vivo molecular imaging applications. Rapid tetrazine cycloadditions allow modular labeling of small molecules with the most commonly used positron emission tomography isotope, (18)F. Additionally, recent work has applied this reaction directly in vivo for the pretargeted imaging of solid tumors. Future work with tetrazine cycloadditions will undoubtedly lead to optimized protocols, improved probes, and additional biomedical applications.

ChemInform Abstract: Studies Directed Towards the Synthesis of Taxol: Preparation of C-13 Oxygenated Taxane Congeners.

Abstract The application of the intramolecular dioxenone photocycloaddition to the synthesis of C-13 oxygenated taxol analogs is described.

ChemInform Abstract: Highly Stereocontrolled Asymmetric Syntheses of Taxol and Taxotere C- 13 Side-Chain Analogues.

Abstract Asymmetric aldol reaction of (+)-tricarbonyl(η 6 -2-trimethylsilylbenzaldehyde)chromium(0) complex ( 4 ) with titanium enolate of S-tert -butyl benzyloxyethanethioate ( 10 ) provided, after consecutive desilylation and decomplexation, anti -aldol product 15 in a highly stereoselective manner. Anti -product 15 was subsequently converted to (2R,3S)- N -benzoyl- and N-tert -butoxycarbonyl-3-phenylisoserine methyl esters ( 23 and 24 ), C-13 side chain analogues of taxol ( 1 ) and taxotere ( 2 ).

ChemInform Abstract: Synthesis of Extremely Simplified Compounds Possessing the Key Pharmacophore Units of Taxol, Phenylisoserine and Oxetane Moieties.

Straight chain compounds having a phenylisoserine unit and an oxetane ring at the alpha- and omega- position, respectively as extremely simplified analogues of taxol were prepared. None of these compounds showed promising tubulin inhibitory activity.

Structure-Activity Relationship of Taxol Inferring from Docking Taxol Analogues to Microtubule Binding Site

In order to find the minimal structural requirements to maintain microtubule binding, 12 taxol analogues have been docked to the taxol binding site of tubulin. By comparing the interactions of each analogue with beta-tubulin, the structure-activity relationships are summarized as follow: C-2 benzoyl and taxane ring systems are the essential groups for microtubule binding, the improvements of bioactivity and bioavailability are dependent on the substituents at positions C-1, C-4, C-7, C-9, C-10, and C-14, whereas the C-13 side chain mainly provides a specific binding.

Biotechnological Production of Taxol and Related Taxoids: Current State and Prospects

Taxol is one of the most effective anti-cancer drugs ever developed. The natural source of taxol is the inner bark of several Taxus species, but it accumulates at a very low concentration and with a prohibitively high cost of extraction. Another problem is that the use of inner bark for taxol production implies the destruction of yew trees. For all these reasons, the growing demand for taxol greatly exceeds the supply that can be sustained by isolation from its natural source and alternative sources of the drug are being sought. Although taxol has been prepared by total synthesis, the process is not commercially viable. Taxol can also be semisynthetically produced via the conversion of baccatin III or 10-deacethylbaccatinIII found in Taxus needles but the cost and difficulty of the extraction process of the semisynthetic precursors are also very high. The most promising approach for the sustainable production of taxol and related taxoids is provided by plant cell cultures at an industrial level. Taxol is currently being clinically used against different tumour processes but due to the difficulty of its extraction and formulation, as well as the growing demand for the compound, new taxol analogues with improved properties are being studied. In this revision we discuss current research in the design of new taxol-related compounds, the chemical structure/anti-cancer activity relationship and new formulations of the drug. We also consider the optimizing strategies to improve taxol and related taxoid production in cell cultures, as well as the current knowledge of taxol metabolism, all of which are illustrated with examples, some of them from our own research.

Structural studies of taxol analogues for drug discovery

Background: The major mechanism of action of antitumor taxanes, including two clinically useful antitumor agents, paclitaxel and docetaxel, lies in their interactions with β-tubulin in microtubule polymers, leading to cell cycle arrest and apoptosis. However, owing to the technical limitations, the molecular interactions of ligands with the residues in taxane binding sites of tubulin as well as the conformations adopted by taxanes on binding are still not fully understood. Objective: This review focuses on the exploration of paclitaxel's interactions with tubulin, and the impact of such efforts on the drug discovery for new taxanes and microtubule stabilizing agents (MSAs). Methods: Data were identified through the search of Chemical s and PubMed databases for research articles and reviews up to April 2008. Conclusion: Based on a collection of information gathered from crystallography, 1D and 2D NMR spectroscopy (NOESY, ROESY, REDOR), and structural–activity relationship (SAR) by chemical synthesis and pharmacological assays, ‘opened’ or T-shape conformations have been predicted to be the biologically active ones in recent years, and confirmed by further SAR studies. Some more potent analogues than paclitaxel or simplified compounds with similar potencies to that of paclitaxel have been discovered. Structural studies of taxol analogues will continue to make great contributions to the rational design of taxanes and novel prototype MSAs for drug discovery.

Design, synthesis and bioactivity of simplified taxol analogues on the basis of bicyclo[3.3.1]nonane derivatives

Four specially designed bicyclo[3.3.1]nonane-based structures were synthesised and found to be cytotoxic at micromolar concentrations and to cause slight non-specific tubulin aggregation.

Microtubule stabilization specifies initial neuronal polarization

Axon formation is the initial step in establishing neuronal polarity. We examine here the role of microtubule dynamics in neuronal polarization using hippocampal neurons in culture. We see increased microtubule stability along the shaft in a single neurite before axon formation and in the axon of morphologically polarized cells. Loss of polarity or formation of multiple axons after manipulation of neuronal polarity regulators, synapses of amphids defective (SAD) kinases, and glycogen synthase kinase-3β correlates with characteristic changes in microtubule turnover. Consistently, changing the microtubule dynamics is sufficient to alter neuronal polarization. Application of low doses of the microtubule-destabilizing drug nocodazole selectively reduces the formation of future dendrites. Conversely, low doses of the microtubule-stabilizing drug taxol shift polymerizing microtubules from neurite shafts to process tips and lead to the formation of multiple axons. Finally, local stabilization of microtubules using a photoactivatable analogue of taxol induces axon formation from the activated area. Thus, local microtubule stabilization in one neurite is a physiological signal specifying neuronal polarization.

A new taxol analogue from the leaves of Taxus cuspidata

A new taxol analogue from the leaves of Taxus cuspidata