scholarly journals Studies Towards the Synthesis of Peloruside A

2021 ◽  
Author(s):  
◽  
Bridget Louise Stocker
Keyword(s):  
Cell Division ◽  
Anticancer Agents ◽  
Aldol Reactions ◽  
Valuable Insight ◽  
Silyl Ether ◽  
Peloruside A ◽  
Initial Strategy ◽  
Acid Fragment ◽  
Retrosynthetic Analysis ◽  
New Treatments

<p>In the search for new treatments for cancer, advances in biology have provided targets for the destruction of cancer cells. One such structure the microtubule, a protein required for cell division, has been the target of many successful anticancer agents including the multi-million dollar earning Taxol [trademark] (paclitaxel) and the epothilones, currently in late-stage clinical trials. More recently it has been shown that peloruside A 1, a secondary metabolite isolated from the New Zealand marine sponge Mycale hentscheli, prevents cell division by stabilising microtubules, and thus offers promise as a novel anticancer agent. However, due to its limited natural abundance, significant quantities of peloruside A can only be obtained through chemical synthesis. A retrosynthetic analysis of peloruside A divided the molecule into four key fragments: a) the commercially available C-l to C-2 benzyloxy acetic acid fragment; b) the C-3 to C-7 fragment; c) the C-8 to C-11 fragment and d) the remaining C-12 to C-24 portion of the macrocycle and side chain. The C-3 to C-7 and C-8 to C-11 fragments combine to form a key intermediate pyranose ring. This thesis however, addresses the synthesis of two of these key fragments, namely the C-8 to C-11 and C-12 to C-24 fragments. An efficient synthesis of the C-8 to C-11 fragment of peloruside A, starting from commercially available pantolactone, has been developed. This synthesis proceeds in good overall yield, and has been successfully reproduced on the multigram scale. The significant portion of this thesis, however, is dedicated to the synthesis of the C-12 to C-24 fragment. After our initial strategy proved unviable, a short, facile method for the synthesis of the C-12 to C-24 fragment, involving the formation of a bis-silyl ether, was developed. The protocol for its desired coupling, via a boron_mediated, remote 1,5-anti-induction aldol reaction has also been established. These and subsequent studies provided valuable insight into the origin of 1,5-anti induction in boron-mediated aldol reactions.</p>

scholarly journals Studies Towards the Synthesis of Peloruside A

2021 ◽  
Author(s):  
◽  
Bridget Louise Stocker
Keyword(s):  
Cell Division ◽  
Anticancer Agents ◽  
Aldol Reactions ◽  
Valuable Insight ◽  
Silyl Ether ◽  
Peloruside A ◽  
Initial Strategy ◽  
Acid Fragment ◽  
Retrosynthetic Analysis ◽  
New Treatments

<p>In the search for new treatments for cancer, advances in biology have provided targets for the destruction of cancer cells. One such structure the microtubule, a protein required for cell division, has been the target of many successful anticancer agents including the multi-million dollar earning Taxol [trademark] (paclitaxel) and the epothilones, currently in late-stage clinical trials. More recently it has been shown that peloruside A 1, a secondary metabolite isolated from the New Zealand marine sponge Mycale hentscheli, prevents cell division by stabilising microtubules, and thus offers promise as a novel anticancer agent. However, due to its limited natural abundance, significant quantities of peloruside A can only be obtained through chemical synthesis. A retrosynthetic analysis of peloruside A divided the molecule into four key fragments: a) the commercially available C-l to C-2 benzyloxy acetic acid fragment; b) the C-3 to C-7 fragment; c) the C-8 to C-11 fragment and d) the remaining C-12 to C-24 portion of the macrocycle and side chain. The C-3 to C-7 and C-8 to C-11 fragments combine to form a key intermediate pyranose ring. This thesis however, addresses the synthesis of two of these key fragments, namely the C-8 to C-11 and C-12 to C-24 fragments. An efficient synthesis of the C-8 to C-11 fragment of peloruside A, starting from commercially available pantolactone, has been developed. This synthesis proceeds in good overall yield, and has been successfully reproduced on the multigram scale. The significant portion of this thesis, however, is dedicated to the synthesis of the C-12 to C-24 fragment. After our initial strategy proved unviable, a short, facile method for the synthesis of the C-12 to C-24 fragment, involving the formation of a bis-silyl ether, was developed. The protocol for its desired coupling, via a boron_mediated, remote 1,5-anti-induction aldol reaction has also been established. These and subsequent studies provided valuable insight into the origin of 1,5-anti induction in boron-mediated aldol reactions.</p>

scholarly journals Unusual Structural Features in the Adduct of Dirhodium Tetraacetate with Lysozyme

2021 ◽  
Vol 22 (3) ◽  
pp. 1496
Author(s):  
Domenico Loreto ◽  
Giarita Ferraro ◽  
Antonello Merlino
Keyword(s):  
Anticancer Agents ◽  
Structural Features ◽  
Side Chain ◽  
Side Chains ◽  
Valuable Insight ◽  
Experimental Conditions ◽  
Egg White Lysozyme ◽  
Potential Applications ◽  
Model Protein ◽  
Hen Egg White

The structures of the adducts formed upon reaction of the cytotoxic paddlewheel dirhodium complex [Rh2(μ-O2CCH3)4] with the model protein hen egg white lysozyme (HEWL) under different experimental conditions are reported. Results indicate that [Rh2(μ-O2CCH3)4] extensively reacts with HEWL:it in part breaks down, at variance with what happens in reactions with other proteins. A Rh center coordinates the side chains of Arg14 and His15. Dimeric Rh–Rh units with Rh–Rh distances between 2.3 and 2.5 Å are bound to the side chains of Asp18, Asp101, Asn93, and Lys96, while a dirhodium unit with a Rh–Rh distance of 3.2–3.4 Å binds the C-terminal carboxylate and the side chain of Lys13 at the interface between two symmetry-related molecules. An additional monometallic fragment binds the side chain of Lys33. These data, which are supported by replicated structural determinations, shed light on the reactivity of dirhodium tetracarboxylates with proteins, providing useful information for the design of new Rh-containing biomaterials with an array of potential applications in the field of catalysis or of medicinal chemistry and valuable insight into the mechanism of action of these potential anticancer agents.

scholarly journals Synthesis of Novel Pyran Fragments to Incorporate into Peloruside Analogues

2021 ◽  
Author(s):  
◽  
Oliver Bayley
Keyword(s):  
Cell Division ◽  
Scale Up ◽  
Great Promise ◽  
Peloruside A ◽  
Bioactive Secondary Metabolite ◽  
Mycale Hentscheli ◽  
Significant Attention ◽  
Simple Carbohydrate

<p>Cancer is currently the second largest cause of death globally, leading to a high demand for new and effective chemotherapeutics. For years, natural products have been used as a source of new bioactive compounds; of particular interest in this context, as a source of new chemotherapeutics. One chemotherapeutic candidate which has attracted significant attention in synthetic and medicinal chemistry communities, is peloruside A. Peloruside A is a bioactive secondary metabolite isolated from the New Zealand marine sponge Mycale hentscheli. Since its discovery, peloruside A has shown great promise in cancer studies both in vivo and in vitro with effects observed even at nanomolar concentrations. These chemotherapeutic effects have been shown to occur by halting cell division at the G2/M checkpoint via microtubule stabilisation. Of particular interest is that this stabilisation occurs in a manner distinct from that of the already established taxane class of microtubule stabilising drugs. This means that peloruside A is able to offer both inhibition of cell division in Taxol® resistant cells and synergistic inhibition alongside the current taxane drugs. Since peloruside A is not abundantly available from its natural source, there is a strong incentive for the development of new synthetic strategies for peloruside A production. Unfortunately attempts at aquaculture and attempts at developing an industrial scale synthesis have both proven unsuccessful thus far. In an attempt to overcome some of the difficulties with the scale up of peloruside, analogues have been developed that are intended to have similar bioactivity to peloruside A but simpler, more concise, synthetic routes. These analogues will also enable further elucidation of the binding properties of peloruside A. This project focuses on the generation of a functionalised pyran fragment, starting from a simple carbohydrate, that may be incorporated into the proposed analogues.</p>

scholarly journals Combinatorial Library Designing and Virtual Screening of Cryptolepine Derivatives against Topoisomerase II by Molecular Docking

2020 ◽  
Author(s):  
Maria ◽  
Zahid Khan
Keyword(s):  
Molecular Docking ◽  
Cell Division ◽  
Binding Energy ◽  
Cancer Cells ◽  
Anticancer Agents ◽  
Combinatorial Library ◽  
Topoisomerase Ii ◽  
Computational Study ◽  
Binding Energies ◽  
Potential Inhibitors

AbstractComputational approaches have emerging role for designing potential inhibitors against topoisomerase 2 for treatment of cancer. TOP2A plays a key role in DNA replication before cell division and thus facilitates the growth of cells. This function of TOP2A can be suppressed by targeting with potential inhibitors in cancer cells to stop the uncontrolled cell division. Among potential inhibitors cryptolepine is more selective and has the ability to intercalate into DNA, effectively block TOP2A and cease cell division in cancer cells. However, cryptolepine is non-specific and have low affinity, therefore, a combinatorial library was designed and virtually screened for identification of its derivatives with greater TOP2A binding affinities.A combinatorial library of 31114 derivatives of cryptolepine was formed and the library was virtually screened by molecular docking to predict the molecular interactions between cryptolepine derivatives and TOP2A taking cryptolepine as standard. The overall screening and docking approach explored all the binding poses of cryptolepine for TOP2A to calculate binding energy. The compounds are given database number 8618, 907, 147, 16755, and 8186 scored lowest binding energies of −9.88kcal/mol, −9.76kcal/mol, −9.75kcal/mol, −9.73kcal/mol, and −9.72kcal/mol respectively and highest binding affinity while cryptolepine binding energy is −6.09kcal/mol. The good binding interactions of the derivatives showed that they can be used as potent TOP2A inhibitors and act as more effective anticancer agents than cryptolepine itself. The interactions of derivatives with different amino acid residues were also observed. A comprehensive understanding of the interactions of proposed derivatives with TOP2A helped for searching more novel and potent drug-like molecules for anticancer therapy. This Computational study suggests useful references to understand inhibition mechanisms that will help in the modification of TOP2A inhibitors.

scholarly journals Fluorescence-Guided Resection of Malignant Glioma with 5-ALA

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Sadahiro Kaneko ◽  
Sadao Kaneko
Keyword(s):  
Malignant Glioma ◽  
Anticancer Agents ◽  
Aminolevulinic Acid ◽  
Malignant Gliomas ◽  
Protoporphyrin Ix ◽  
Time Spectrum ◽  
Photodynamic Diagnosis ◽  
Promising Technique ◽  
New Methods ◽  
New Treatments

Malignant gliomas are extremely difficult to treat with no specific curative treatment. On the other hand, photodynamic medicine represents a promising technique for neurosurgeons in the treatment of malignant glioma. The resection rate of malignant glioma has increased from 40% to 80% owing to 5-aminolevulinic acid-photodynamic diagnosis (ALA-PDD). Furthermore, ALA is very useful because it has no serious complications. Based on previous research, it is apparent that protoporphyrin IX (PpIX) accumulates abundantly in malignant glioma tissues after ALA administration. Moreover, it is evident that the mechanism underlying PpIX accumulation in malignant glioma tissues involves an abnormality in porphyrin-heme metabolism, specifically decreased ferrochelatase enzyme activity. During resection surgery, the macroscopic fluorescence of PpIX to the naked eye is more sensitive than magnetic resonance imaging, and the alert real time spectrum of PpIX is the most sensitive method. In the future, chemotherapy with new anticancer agents, immunotherapy, and new methods of radiotherapy and gene therapy will be developed; however, ALA will play a key role in malignant glioma treatment before the development of these new treatments. In this paper, we provide an overview and present the results of our clinical research on ALA-PDD.

scholarly journals Broad-spectrum survey of medicinal plants as a potential source of anticancer agents

2022 ◽  
Vol 21 (1) ◽  
pp. 1-40
Author(s):  
K Saranya ◽  
◽  
V Manivasagan ◽  
K Gopi ◽  
K Karthik ◽  
...  
Keyword(s):  
Cell Division ◽  
Side Effects ◽  
Medicinal Plants ◽  
Broad Spectrum ◽  
Anticancer Agents ◽  
Cancer Treatments ◽  
Potential Source ◽  
African Populations ◽  
Different Types ◽  
Different Parts

Cancer is an abnormal and uncontrolled growth of cells that spreads through cell division. There are different types of medicines available to treat cancers, but no drug is found to be fully effective and safe for humans. The major problem involved in the cancer treatments is the toxicity of the established drug and their side effects. Medicinal plants are used as folk medicines in Asian and African populations for thousands of years. 60% of the drugs for treating cancer are derived from plants. More than 3000 plants have anticancer activity. The present review aims at the study of a broad spectrum survey of plants having anticancer components for different type of cancers. This article consists of 364 medicinal plants and their different parts as potential Source of Anticancer Agents.

scholarly journals Towards a Total Synthesis of Peloruside A and the Preparation of Selected Inositol Derivatives

2021 ◽  
Author(s):  
◽  
Sylvia Myrna Baars
Keyword(s):  
Total Synthesis ◽  
Large Scale ◽  
Leishmania Donovani ◽  
Process Development ◽  
Scale Up ◽  
Significant Inhibition ◽  
Pyranose Ring ◽  
Peloruside A ◽  
Asymmetric Aldol ◽  
Retrosynthetic Analysis

<p>This thesis covers two broad areas of work under the general theme of the synthesis of bioactive and/or synthetically useful compounds based on natural products or deriving from the chiral pool. Chapters one, two and three focus on the marine secondary metabolite peloruside A (1), which has been shown to stabilise microtubules during mitosis and hence cause apoptosis (cell death) in a similar manner to the very successful anticancer drug Taxol. A synthetic program with the aim of devising a total synthesis was initiated at Victoria University of Wellington after peloruside A's discovery in 1999. Four synthetic disconnects were identified in the retrosynthetic analysis of peloruside A: to give the C-l to C-2 fragment; the C-3 to C-7 fragment; the C-8 to C-11 fragments; and the C-12 to C-24 fragment. The C-7 to C-8 bond was to be formed via an asymmetric aldol reaction to give the pyranose ring fragment (highlighted in blue). In this thesis, the synthesis of the C-3 to C-7 fragment is described. A1do1 reactions with the C-8 to C- 11 ketone have been investigated, and subsequent progress towards the assembly of the pyranose ring fragment is presented. Chapters four, five, six and seven describe the preparation of selected synthetically and biologically useful derivatives of the commercially available inositols, quebrachitol (L-chiro-inositol-2-methyl ether) and myo-inositol. The butane di-acetal (BDA) derivatives 293, 300, and 301 (as well as acetylated and methylated derivatives thereof) were prepared during work directed towards the synthesis of the inositol core of a phosphatidylinositol manno-oligosaccharide (PIM-6) isolated from Mycobacterium bovis and M. smegmatis. Quebrachitol derivatives 305, 306 and 307 were prepared and subsequently tested against myoinositol (the optimal competitor) in biological uptake assays of the microorganisms, Candida albicans and Leishmania donovani. For both microorganisms, the mono- and di-O-methylated L-chiro-inositol derivatives 307 and 305, as well as quebrachitol, gave significant inhibition results, with P values from P < 0.001 to P < 0.05 for paired-sample t-test analyses, i.e.99.9% to 95% confidence for significant inhibition, respectively. The benzoylated derivative 306 did not induce any inhibition of myo-inositol uptake. Myo-inositol is the most abundant of the inositols in nature and is readily available. However, as it is a meso compound, one of the key challenges in the use of myoinositol as a synthetic precursor is an efficient resolution method. The formation of myo-inositol camphanylidene acetal 269a is one successful solution, and work done in an attempt to better understand the selectivity of the reaction is reported here. Also, process development work was done to adapt the preparation so that it was suitable for scale-up, and a subsequent large scale synthesis of the acetal was undertaken. Previously unpublished X-ray crystal structures were obtained for 269a and, for two of the diastereomeric impurities of the reaction.</p>

scholarly journals Mechanistic Investigation of 1,5-Anti Stereoinduction in Aldol Reactions

2021 ◽  
Author(s):  
◽  
Xuyu Liu
Keyword(s):  
Variable Temperature ◽  
Aldol Reaction ◽  
Underlying Mechanism ◽  
Membered Ring ◽  
Aldol Reactions ◽  
Peloruside A ◽  
Mechanistic Investigation ◽  
Relative Stereochemistry ◽  
Mycale Hentscheli ◽  
Key Questions

<p>Peloruside A (+)-1 is a novel secondary metabolite isolated from a New Zealand marine sponge (Mycale hentscheli) by Northcote and West of Victoria University. Because it has a polyketide backbone, aldol reactions have been widely employed for its total synthesis. Aldol reactions displaying 1,5-anti stereoinduction mediated by the C₁₅ stereocenter (according to peloruside A numbering) have proven useful for the synthesis of the C₁₁–C₁₂ bond of peloruside A and analogues. This project is the continuation of Stocker's and Turner's studies on the excellent stereoinduction of 2 in boron-mediated aldol reactions. The relative stereochemistry of the corresponding aldol product is consistence with the expectations of Kishi's C database for a 1,5-anti product. Furthermore, the diphenylsilyl acetal tethered eight-membered ring of 2 has proven to be essential for its stereoinduction, while the homoallylic oxygen does not appear to play a significant role.  Although 1,5-anti aldol reactions have been used frequently in the syntheses of polyketidederived natural products, the underlying mechanism for the 1,5-anti-stereoinduction remains inconclusive. Three models have been proposed, including Hoberg's π-stacking model, Goodman's hydrogen-bonding model, and a modification of Abiko's diborylated model. The underlying mechanism for the stereoinduction of 2 was investigated using variable temperature NMR, 1D NOESY and 1D ROESY experiments. It was found that Hoberg's and Abiko's models are not able to explain the stereoinduction of 2 and that Goodman's model used for explaining the transition states of the aldol reaction of β-trimethylsilyloxy methyl ketones is also not suitable.  A modification of Goodman's model has been proposed to explain the excellent 1,5-anti stereoinduction of 2. While attempts to couple 2 and 3 to a variety of bulky aldehydes bearing groups with different steric and electronic factors in boron-mediated aldol reactions were unsuccessful, the reaction of 3 with 4-bromobenzaldehyde using TiCl₄ and DIPEA afforded an excellent yield (>99%) of the aldol product. This revealed the six-membered ring in the TS of the boron-mediated aldol reaction is too compact for 2 and 3. However, it was found that 2 is incompatible with TiCl₄. Key questions regarding the 1,5-anti-stereoinduction of 2 have been answered and a modified procedure for the NMR investigation of an aldol reaction is described in this thesis.</p>

Combinatorial library design and virtual screening of cryptolepine derivatives against topoisomerase IIA by molecular docking and DFT studies

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Maria ◽  
Zahid Khan ◽  
Aleksey E. Kuznetsov
Keyword(s):  
Molecular Docking ◽  
Cell Division ◽  
Binding Energy ◽  
Cancer Cells ◽  
Anticancer Agents ◽  
Combinatorial Library ◽  
Computational Study ◽  
Binding Energies ◽  
Binding Affinities ◽  
Potential Inhibitors

Abstract Various computational approaches have received ever-growing role in the design of potential inhibitors of the topoisomerase 2 (TOP2A) for cancer treatment. TOP2A plays a key role in the deoxyribonucleic acid (DNA) replication before cell division and thus facilitates the growth of cells. This TOP2A function can be suppressed by targeting it with potential inhibitors in cancer cells to terminate the uncontrolled cell division. Among potential inhibitors, cryptolepine has higher selectivity along with the ability to intercalate into DNA, effectively blocking TOP2A and ceasing cell division in cancer cells. However, this compound has drawbacks of being nonspecific and possessing relatively low affinity. Therefore, a combinatorial library of 31,114 cryptolepine derivatives was designed and virtually screened by molecular docking to predict the molecular interactions between the cryptolepine derivatives and TOP2A using cryptolepine as a standard. All the binding poses of cryptolepine derivatives for TOP2A were investigated to calculate binding energy. The compounds with the database numbers 8618, 907, 147, 16755, and 8186 scored the highest binding energies, −9.88, −9.76, −9.75, −9.73, and −9.72 kcal/mol, respectively, and the highest binding affinities while the cryptolepine binding energy is −6.09 kcal/mol. The strong binding interactions of these derivatives show that they can be used as potent TOP2A inhibitors and act as more effective anticancer agents than cryptolepine itself. The interactions of these derivatives with different amino acid residues were also observed and analyzed. A comprehensive understanding of the interactions of the proposed derivatives with TOP2A helped for searching more novel and potent drug-like molecules for anticancer therapy. This computational study suggests useful references to understand inhibition mechanisms that will help in the further modifications of TOP2A inhibitors. Moreover, the DFT study of the derivatives with the highest binding energies was performed, helping to further understand the binding affinities of these compounds.

scholarly journals Microtubules and Actin Cytoskeleton of Cryptococcus neoformans as Targets for Anticancer Agents to Potentiate a Novel Approach for New Antifungals

Chemotherapy ◽  
2015 ◽  
Vol 61 (3) ◽  
pp. 117-121 ◽  
Author(s):  
Marie Kopecká
Keyword(s):  
Cell Division ◽  
Actin Cytoskeleton ◽  
Cryptococcus Neoformans ◽  
Anticancer Agents ◽  
Pathogenic Yeast ◽  
Yeast Extract Peptone Dextrose ◽  
Cell Counts ◽  
Novel Approach ◽  
Latrunculin A ◽  
Actin Cables

Background: We investigated the targeting of microtubules (MT) and F-actin cytoskeleton (AC) of the human pathogenic yeast Cryptococcus neoformans with agents for cancer therapy, in order to examine whether this yeast cytoskeleton could become a new antifungal target for the inhibition of cell division. Methods: Cells treated with 10 cytoskeleton inhibitors in yeast extract peptone dextrose medium were investigated by phase-contrast and fluorescence microscopy, and growth inhibition was estimated by cell counts using a Bürker chamber and measuring absorbance for 6 days. Results: Docetaxel, paclitaxel, vinblastine sulfate salt, cytochalasin D and chlorpropham [isopropyl N-(3-chlorophenyl) carbamate] did not inhibit proliferation. The MT inhibitors methyl benzimidazole-2-ylcarbamate (BCM), nocodazole, thiabendazole (TBZ) and vincristine (VINC) disrupted MT and inhibited mitoses, but anucleated buds emerged on cells that increased in size, vacuolated and seemed to die after 2 days. The response of the cells to the presence of the actin inhibitor latrunculin A (LA) included the disappearance of actin patches, actin cables and actin rings; this arrested budding and cell division. However, in 3-4 days, resistant budding cells appeared in all 5 inhibitors. Disruption of the MT and AC and inhibition of cell division and budding persisted only when the MT and AC inhibitors were combined, i.e. VINC + LA, BCM + LA or TBZ + LA. Conclusion: The MT and AC of C. neoformans are new antifungal targets for the persistent inhibition of cell division by combined F-actin and MT inhibitors.

Sign in / Sign up

Export Citation Format

Share Document