Diversity through semisynthesis: the chemistry and biological activity of semisynthetic epothilone derivatives
read more
Citations
Use of a biosynthetic intermediate to explore the chemical diversity of pseudo-natural fungal polyketides
Comprehensive Structure-Activity Relationship Studies of Macrocyclic Natural Products Enabled by Their Total Syntheses.
Modular construction of a functional artificial epothilone polyketide pathway.
Heterologous Production and Yield Improvement of Epothilones in Burkholderiales Strain DSM 7029
Molecules of Natural Origin, Semi-synthesis and Synthesis with Anti-Inflammatory and Anticancer Utilities
References
Plant antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia.
Promotion of microtubule assembly in vitro by taxol
The Role of Natural Product Chemistry in Drug Discovery
Epothilones, a New Class of Microtubule-stabilizing Agents with a Taxol-like Mechanism of Action
Paclitaxel-resistant Human Ovarian Cancer Cells Have Mutant β-Tubulins That Exhibit Impaired Paclitaxel-driven Polymerization
Related Papers (5)
Frequently Asked Questions (15)
Q2. How did the thiazole side chain be converted to methylene?
While 59 could be converted to methylene derivative 60 in a modest overall yield of 15% (after deprotection), all attempts to re-introduce the natural thiazole side chain or to create a phenyl-based Epo A analog using Wittig-type chemistry were unsuccessful [47,71,75].
Q3. What is the important aspect of the biochemical activity of epothilones?
The earliest contributions to this area stem from the GBF group and involved the transformation of epothilonesA, B, and C (vide infra) into a variety of C12/C13-modified derivatives [23].
Q4. What are the prominent of these new microtubule stabilizers?
Most prominent among these new microtubule stabilizers are the epothilones, which are bacteria-derived macrolides whose microtubule-stabilizing properties were discovered in 1996 by a group at Merck Research Laboratories [7]; the compounds themselves, however, had been first isolated 9 years earlier from the myxobacterium Sorangium cellulosum Sc 90 by Reichenbach and Höfle (Fig. 2) [8,9].
Q5. What is the resulting derivative of Epo A?
The resulting N-unsubstituted 12,13-aziridinyl-Epo A 21 has been converted into a series of N-substituted derivatives via alkylation, acylation, carbamoylation, or sulfonylation.
Q6. How much of the epothilone derivatives can be obtained by electrophilic?
While not accessible by base treatment and subsequent electrophilic quenching, C21-substituted epothilone derivatives can nevertheless be obtained through semisynthesis in a very efficient manner.
Q7. What is the simplest method of establishing the controlled degradation of Epo C into ester?
Employing PLE-catalyzed hydrolysis of the lactone group and subsequent cleavage of the C12/C13 double bond by ozonolysis, the BMS group was able to establish the controlled degradation of Epo C into ester 82 (Scheme 20).
Q8. What is the way to reduce the hydroxyl group in Epo A?
Selective oxidation of the hydroxyl group on C3 in Epo A is more difficult and could only be accomplished in very moderate yield with a mixture of dimethylsulfide and dibenzoylperoxide [47].
Q9. What is the IC50 value of oxazoline 13?
The phenyl-substituted oxazoline 13 was found to inhibit human cancer cell growth in vitro with IC50 values around 20 nM [48]; thus, the activity of this analog is within a 10- fold range of the activity of Epo A and it is comparable with the activity of cyclic acetals 5a and 9a (vide supra).
Q10. What is the effect of the pyridyl derivative 14 on cell growth?
It is, therefore, unclear to what extent (if at all) the enhanced cellular activity of 14 (over 13) is a result of higher affinity interactions with the tubulin/microtubule system (possibly through H-bond formation between the pyridine nitrogen and a donor group on the protein).
Q11. What is the way to convert Epo A to a whole range of analogs?
In addition to cyclopropyl-epothilones, the BMS group has also devised a strategy for the conversion of Epo A to a whole range of analogs incorporating a (substituted) aziridine ring in place of the epoxide moiety [45].
Q12. What is the IC50 of the cyclopropyl-epo B?
Bis-substitution of the oxygen-replacing carbon in cyclopropyl-Epo B by bulky bromine substituents leads to reduced activity, but the resulting analog is still more potent than Epo D against the HCT-116 cell line (IC50 against HCT116 of 3.8 nM versus 6.5 nM for Epo D [49]).
Q13. What is the first implementation of this concept?
The first implementation of this concept was reported by the GBF group, who used ring-opening olefin metathesis (ROM) with ethylene for the conversion of Epo C into the ring-opened product 69 in 73% yield (employing Grubbs II catalyst) [73] (Scheme 18).
Q14. What is the reason for the bias towards semisynthesis?
This bias towards semisynthesis reflects the technical (fewer chemical steps) and economic (cost of goods) advantages still associated with natural product derivatization.
Q15. What is the role of the epothilone in the treatment of cancer?
Epo B and a number of its analogs have been demonstrated to possess potent in vivo antitumor activity and at least seven epothilone-type compounds have entered clinical evaluation in humans (although several of these are not anymore under development).