New skeletal rearrangements of C and D rings of a 13-oxobaccatin III derivative (original) (raw)

1998, Tetrahedron

https://doi.org/10.1016/S0040-4020(98)00993-4

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Abstract

13-Oxobaccatin III (4) was oxidized to 7,13-dioxo D-secobaccatin III (5). This compound, when treated with base or cyanide ion, underwent rearrangements involving the rupture of the C-7,C-8 bond, the migration of the benzoyl and acetyl groups and intramolecular formation of new rings. Four new compounds were isolated and fully characterized. O 1998 Elsevier Science Ltd. All rights reserved.

Synthesis and Structure-Activity Relationships of New Antitumor Taxoids. Effects of Cyclohexyl Substitution at the C-3' and/or C-2 of Taxotere (Docetaxel)

Journal of Medicinal Chemistry, 1994

Synthesis and cytotoxicity of the new analogs (11-13) of docetaxel possessing cyclohexyl groups instead of phenyl groups at the C-3' and/or C-2 benzoate positions are described. The C-2 cyclohexanecarboxylate analog of paclitaxel(15) is also synthesized for comparison. The potency of these new taxoids were examined for their inhibitory activity for microtubule disassembly and also for their cytotoxicity against murine P388 leukemia cell line as well as doxorubicinresistant P388 leukemia cell line (P388Dox). It is found that 3'-dephenyl-3'-cyclohexyldocetaxel (11) (0.7227 and 2-(hexahydro)docetaxel (12) (0.8527 possess strong inhibitory activity for microtubule disassembly equivalent to docetaxel(O.727, which is more potent than paclitaxel (1.027. The results clearly indicate that phenyl or an aromatic group a t (2-3' or C-2 is not a requisite for strong binding to the microtubules. This finding has opened an avenue for development of new nonaromatic analogs of docetaxel and paclitaxel. 3'-DephenyL3'-cyclohexyl-2-(hexahydro)docetaxel (13) (22') turns out to be a substantially weaker inhibitor. The cytotoxicities of 11-13 against P388 are, however, in the same range that is 8-12 times weaker than docetaxel and 4-6 times weaker than paclitaxel, i.e., 13 shows equivalent cytotoxicity to that of 11 or 12 in spite of much lower microtubule disassembly inhibitory activity. The cytotoxicities of these new taxoids against the P388/Dox cell line are only 2-2.5 times lower than that of docetaxel. The potency of 2-(hexahydro)paclitaxel(lS) for these assays is much lower than the docetaxel counterpart 12. The significant loss of activity in vivo against B16 melanoma is observed for 11-13, i.e., 11 is only marginal (T/C = 38% at 20 mg/kg/day), and 12 and 13 are inactive (T/C = 76% and 79%, respectively). This could be ascribed to faster metabolism, faster excretion or other bioavailability problems. * Rhhe-Poulenc Rorer.

Synthesis of biologically active 2-benzoyl paclitaxel analogues

Bioorganic & Medicinal Chemistry Letters, 1995

... MM Gharpure, JM Rimoldi, DGI Kingston, YQ Jiang and E. Hamel. Tetrahedron Lett. 35 (1994), p. 6839. Abstract | PDF (339 K) | View Record in Scopus | Cited By in Scopus (25). (12). For the synthesis and biological activity of heteroaromatic 2-benzoyl paclitaxel analogues see: ...

Synthesis and Biological Evaluation of 2-Acyl Analogues of Paclitaxel (Taxol)

J. Med. …, 1998

The anticancer drug paclitaxel (Taxol) has been converted to a large number of 2-debenzoyl-2-aroyl derivatives by three different methods. The bioactivities of the resulting analogues were determined in both tubulin polymerization and cytotoxicity assays, and several analogues with enhanced activity as compared with paclitaxel were discovered. Correlation of cytotoxicity in three cell lines with tubulin polymerization activity showed reasonable agreement. Among the cell lines examined, the closest correlation with antitubulin activity was observed with a human ovarian carcinoma cell line.

Synthesis and bioactivities of paclitaxel analogs with a cyclopropanated side-chain

Tetrahedron Letters, 2003

Four paclitaxel analogs with a cyclopropanated side-chain were synthesized by coupling of the spirocyclopropanated oxazoline-5-carboxylic acid 4 with 7-TES-baccatin III, followed by hydrolytic ring opening and rearrangement. The absolute configuration of the 2%-position was determined by NMR analysis of the corresponding Mosher esters. The two new paclitaxel analogs with the R configuration at C-2% were both active in the A2780 mammalian cell line cytotoxicity assay, but much less than paclitaxel itself.

Bridging Converts a Noncytotoxic nor- Paclitaxel Derivative to a Cytotoxic Analogue by Constraining It to the T-Taxol Conformation

Organic Letters, 2006

Supporting Data A. Synthesis 2′-Triisopropylsiloxy-7-triethylsiloxy-bridged-11(15→1)-abeo-paclitaxel (8). Pyridine (0.15 mL) was added to a solution of 7 (18 mg) in anhydrous CH 2 Cl 2 (5 mL). The mixture was cooled to-20 °C and thionyl chloride (53 μL) was added. After stirring for 0.5 h, the reaction was quenched with saturated aqueous NaHCO 3 and extracted with EtOAc. The organic phase was dried under vacuum and the residue was separated by PTLC on silica gel, developed with 8% EtOAc in hexane, to give compound 8 (8.5 mg, 49%) as a white solid. 1 H NMR δ 7.99 (2H, d, J

Recent Advances in Structure Modifications of Taxol (Paclitaxel)

Indian Journal of Chemistry Section B-organic Chemistry Including Medicinal Chemistry, 1997

Taxol (paclitaxel), a complex polyoxygenated diterpene isolated originally from the bark of Taxus brevifolia is a promising anticancer agent in the treatment of ovarian and breast cancer. The molecule has been extensively modified during the last few YC3rsin a bid to enhance its water solubility and to improve its therapeutic profile. The present review gives an account of the recent developments in the structure modifications of taxol and comments on the structure activity relationships of the analogues. Natural products are the organic molecules which are elaborated by living tissues derived from higher plants, fungi, microbes, marine organisms and animals and exhibit a remarkably wide range of chemical diversity and a multiplicity of biological properties. From time immemorial natural resources have been in use for combating human ailments. Over the last fifteen years interest in drugs of plant origin has been reviving and growing steadily, and the drug researchers are exploring the potential of natural products for the cure of still unsurmountable diseases like cancer and AIDS. Cancer is a disease characterised by unregulated proliferation of cells It is a growing public health menace and more than six million new cases of this disease are reported every year. It was in the year 1960 that a systematic screening programme for antineoplastic agents of plant origin was initiated in National Cancer Institute, USA under Dr J.H. Hartwell. Plant samples collected at random by the US Department of Agriculture were supplied for antitumour screening. During such screening, the bark of Pacific yew, Tanis brevifolia, showed activity against a number of cell lines. Using bioactivityguided fractionation, the active principle, then named 'When originally discovered the generic name given was taxol, before marketing Bristol-Myers Squibb Co. in United States retained this name as their registered trademark and a new generic name paclitaxel was given. In the present communication, however, the original name, taxol has been used.

Bridging Converts a Noncytotoxic nor-Paclitaxel Derivative to a Cytotoxic Analogue by Constraining It to the T-Taxol Conformation

Organic Letters, 2006

The synthesis of the bridged A-nor-paclitaxel 4 has been achieved from paclitaxel in a key test of the T-Taxol conformational hypothesis. Although the unbridged A-nor-paclitaxel 3 is essentially non-cytotoxic, the bridged analog 4 is strongly cytotoxic. This result provides strong evidence for the T-Taxol conformation as the bioactive tubulin-binding conformation of paclitaxel. The natural product paclitaxel (PTX) (Taxol™, 1) is a clinically approved drug for several tumor malignancies, 1 and its chemistry and biology have been investigated extensively. 2 It acts by promoting the polymerization of tubulin to stabilized microtubules, leading to apoptotic cell death, 3-456 and its clinical activity is believed to be directly related to this microtubulebinding activity. 6 Since the bioactivity of PTX is intimately connected with its tubulin-assembly properties, and since tubulin assembly is initiated by the non-covalent binding of paclitaxel to tubulin, the nature of this binding is a matter of great interest. In one scenario, a knowledge of the tubulinbinding conformation of paclitaxel would enable the design of simple non-taxoid compounds with comparable binding affinity and bioactivity. DKingston@vt.edu. Supporting Information Available Detailed synthetic procedures for the synthesis of the bridged A-nor-paclitaxel 4 and A-nor-baccatin III 5, 1 H and 13 C NMR spectra of compound 4, tubulin-GTP polymerization by compound 3, tubulin binding curves for 1, 3, and 4, and conformational searching, conformer extraction and binding site docking for 3 and 4. This material is available free of charge via the internet at http://pubs.acs.org.

Novel C-4 paclitaxel (Taxol®) analogs: potent antitumor agents

Bioorganic & Medicinal Chemistry Letters, 1995

A large number of C-4 paclitaxel analogs have been prepared in the course of our systematic C-4 modification. These include C-4 esters, carbonates, carbamates as well as a C-4 deacetyl derivative. All of these analogs were evaluated in a tubulin polymerization assay as well as in a cytotoxicity assay agabzst a human colon cancer cell line. The potent analogs emerging from these in vitro assays were further evaluated in vivo. With the exception of paclitaxel side chain bearing C-4 carbamates and C-4 aromatic esters, most of the C-4 aliphatic esters and carbonates were found to possess comparable or superior activity to paclitaxel in vitro. Several C-4 aliphatic esters and carbonates also exhibited in vivo activities against i.p. implanted murine M-109 lung carcinoma.

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Synthesis of Paclitaxel. 2. Construction of the ABCD Ring and Formal Synthesis

Organic Letters, 2015

A formal synthesis of the antitumor diterpenoid paclitaxel (Taxol) is described. The ABC ring of paclitaxel, synthesized starting from 1,3-cyclohexanedione and tri-Oacetyl-D-glucal by SmI 2-mediated cyclization as the key transformation, was successfully converted to Takahashi's tetracyclic oxetane intermediate. A double Chugaev reaction was employed for introduction of the strained bridgehead olefin, and stereoselective formation of the oxetane ring afforded the known synthetic intermediate, completing the formal synthesis of paclitaxel.

Synthesis and Biological Evaluation ofN-(Arylsulfanyl)carbonyl Analogues of Paclitaxel (Taxol

Chemistry & Biodiversity, 2006

Four new N-(arylsufanyl)carbonyl paclitaxel analogues (2a–d) were prepared from 7-(triethylsilyl)-protected baccatin III (5). Their cytotoxicities against human ovarian (A2780) and prostate cancer (PC3) cell lines, as well as their tubulin-assembly activities, were determined. In these assays, the new compounds showed rather weak activities, one two orders of magnitude below those of paclitaxel (taxol; 1). The known 3′-N-[(thiophen-2-yl)carbonyl] paclitaxel analogue 3 was also prepared. As previously reported, 3 exhibited strongly improved cytotoxicities and tubulin-assembly activities as compared to paclitaxel (1).

Structure−Activity Relationships of Ring C-Secotaxoids. 1. Acylative Modifications †

Journal of Natural Products, 2004

The acylative modification of IDN 5390 (3a), a 7,8-secotaxoid under preclinical development, was investigated. A modest decrease of potency was observed upon acylation of the primary and the enolic hydroxyls, suggesting that, just like in paclitaxel, the hydroxyl groups in the upper right-hand sector are not critical for cytotoxicity. The activity of these analogues, and especially of the chemically robust carbonates 3c and 3d, makes it unlikely that the activity of IDN 5390 is due to in vivo oxidation to a fledgling 7-aldehyde and re-aldolization to the corresponding taxane derivative.

Synthesis and bioactivity of a side chain bridged paclitaxel: A test of the T-Taxol conformation

Bioorganic & Medicinal Chemistry Letters, 2009

A knowledge of the bioactive tubulin-binding conformation of paclitaxel (Taxol™) is crucial to a full understanding of the bioactivity of this important anticancer drug, and potentially also to the design of simplified analogs. The bioactive conformation has been shown to be best approximated by the T-Taxol conformation. As a further test of this conclusion, the paclitaxel analog 4 was designed as a compound which has all the chemical functionality necessary for activity, but which cannot adopt the T-Taxol conformation. The synthesis and bioassay of 4 confirmed its lack of activity, and thus provided further support for the T-Taxol conformation as the bioactive tubulin-binding conformation.

Design and synthesis of de novo cytotoxic alkaloids by mimicking the bioactive conformation of paclitaxel

Bioorganic & Medicinal Chemistry, 2010

Novel paclitaxel-mimicking alkaloids were designed and synthesized based on a bioactive conformation of paclitaxel, i.e., REDOR-Taxol. The alkaloid 2 bearing a 5-7-6 tricyclic scaffold mimics REDOR-Taxol best among the compounds designed and was found to be the most potent compound against several drug-sensitive and drug-resistant human cancer cell lines. MD simulation study on the paclitaxel mimics 1 and 2 as well as REDOR-Taxol bound to the 1JFF tubulin structure was quite informative to evaluate the level of mimicking. The MD simulation study clearly distinguishes the 5-6-6 and 5-7-6 tricyclic scaffolds, and also shows substantial difference in the conformational stability of the tubulin-bound structures between 2 and REDOR-Taxol. The latter may account for the large difference in potency, and provides critical information for possible improvement in the future design of paclitaxel mimics.

Novel D-Seco Paclitaxel Analogues: Synthesis, Biological Evaluation, and Model Testing

The Journal of Organic Chemistry, 2001

Four new D-secopaclitaxel analogues were synthesized from paclitaxel. The key step of the synthesis involved the opening of the D-ring by Jones oxidation. Two of the compounds had been predicted to be nearly as active as paclitaxel in a minireceptor model of the binding site on tubulin, but all were biologically inactive in an in vitro cytotoxic assay and a tubulin assembly assay. The biological results identify a weakness in our predictive minireceptor model and suggest a corrective remedy in which additional amino acids are needed to accommodate ligand-protein steric effects around the oxetane ring. These changes to the model lead to correct predictions of the bioactivity. Conformational analysis and dynamics simulations of the compounds showed that the 4-acetyl substituent is as important as the oxetane in determining the A ring conformation.

Exploration of the Paternò–Büchi Reaction as a Potential Route to the Oxetan Ring of Taxol®

Australian Journal of Chemistry, 1999

Two photochemical pathways to paclitaxel-like oxetan rings have been examined. In the first approach, an intramolecular Paternò–BÜchi reaction on a 6,7-enal was attempted without success. The intermolecular variation using a bicyclic alkene in the presence of either benzaldehyde or acetophenone delivered oxetans whose regiochemistry was the same as that found in paclitaxel but opposite in stereochemistry. The crystal structures of a key intermediate diol and a photochemically generated oxetan are reported.

Synthesis and biological evaluation of C-3′NH/C-10 and C-2/C-10 modified paclitaxel analogues

Bioorganic & Medicinal Chemistry, 2003

Concurrent modifications on the C-3 0 NH/C-10, and C-2/C-10 positions on paclitaxel were carried out as a way of investigating possible synergistic effects. The biological activities of these analogues were evaluated in both a microtubule assembly assay and human ovarian cancer (A2780) and prostate cancer (PC3) cytotoxicity assay. In some cases the doubly modified analogues were more active than would have been predicted based on the activity of the singly modified analogues, indicating probable synergistic effects. #

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Diels Alder Reactions During the Biosynthesis of Sorbicillinoids

Angewandte Chemie International Edition, 2020

The sorbicillinoids are a class of biologically active and structurally diverse fungal polyketides arising from sorbicillin. Through co‐expression of sorA, sorB, sorC, and sorD from Trichoderma reesei QM6a, the biosynthetic pathway to epoxysorbicillinol and dimeric sorbicillinoids, which resemble Diels–Alder‐like and Michael‐addition‐like products, was reconstituted in Aspergillus oryzae NSAR1. Expression and feeding experiments demonstrated the crucial requirement of the flavin‐dependent monooxygenase SorD for the formation of dimeric sorbicillinoids, hybrid sorbicillinoids, and epoxysorbicillinol in vivo. In contrast to prior reports, SorD catalyses neither the oxidation of 2′,3′‐dihydrosorbicillin to sorbicillin nor the oxidation of sorbicillinol to oxosorbicillinol. This is the first report that both the intermolecular Diels–Alder and Michael dimerization reactions, as well as the epoxidation of sorbicillinol are catalysed in vivo by SorD. One for all: The biosynthetic pathway to dimeric sorbicillinoids and epoxysorbicillinol was reconstituted in Aspergillus oryzae NSAR1. Expression and feeding experiments demonstrated that the flavin‐dependent monooxygenase SorD catalyzes epoxidation, Diels–Alder addition, and Michael addition reactions in vivo.

Diels–Alder Reactions During the Biosynthesis of Sorbicillinoids

Angewandte Chemie

The sorbicillinoids are ac lass of biologically active and structurally diverse fungal polyketides arising from sorbicillin. Through co-expression of sorA, sorB,s orC,a nd sorD from Trichoderma reesei QM6a, the biosynthetic pathway to epoxysorbicillinol and dimeric sorbicillinoids,w hich resemble Diels-Alder-like and Michael-addition-like products, was reconstituted in Aspergillus oryzae NSAR1. Expression and feeding experiments demonstrated the crucial requirement of the flavin-dependent monooxygenase SorD for the formation of dimeric sorbicillinoids,h ybrid sorbicillinoids,a nd epoxysorbicillinol in vivo.I nc ontrast to prior reports,S orD catalyses neither the oxidation of 2',3'-dihydrosorbicillin to sorbicillin nor the oxidation of sorbicillinol to oxosorbicillinol. This is the first report that both the intermolecular Diels-Alder and Michael dimerization reactions,aswell as the epoxidation of sorbicillinol are catalysed in vivo by SorD.