Temsirolimus - CAS 162635-04-3

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CAS 162635-04-3 Temsirolimus
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Reference Reading
1. Structure guided design of improved anti-proliferative rapalogs through biosynthetic medicinal chemistry
Matthew A. Gregory, Andrew L. Kaja, Barrie Wilkinson*. Chem. Sci., 2013, 4, 1046–1052
They also showed potent anti-proliferative activity against cancer cell lines with average IC70 values across 37 cell lines of 16.3, 7.4 and 16.8 μM respectively. Thus, the average IC70 of 1 and 4 are indistinguishable, but that for the doubly modified rapalog 8 is >2-fold lower. Previous data have suggested that tumours deficient in the phosphatase and tensin homologue (PTEN) are more sensitive to inhibition of mTOR. It is therefore interesting to note that 8 is more potent than 1 at inhibiting PC3, LNCAP and U87MG, all of which are PTEN null cell lines, whilst it is less potent at inhibition of the PTEN normal cell lines DU145 and SF268. Whether this suggests that compound 8 has a slightly alteredmode of action, whichmay be more dependent on PTEN status, warrants further investigation. Compound 8 also shows >10-fold more potency than 1 against both pancreatic cell lines in the panel (average IC70 4.1μM vs. 41.5μM).We then tested temsirolimus against these two pancreatic cell lines, and generated very similar data to 1 (average IC70 46.4μM). Pancreatic cancers frequently contain activated PI3K/Akt/mTOR pathways. However, whilst preclinical models have shown some potential for use of mTOR inhibition in this notoriously difficult to treat indication, early clinical trials with the rapalogs temsirolimus and everolimus have shown mixed results.
2. Biosynthetic medicinal chemistry of natural product drugs
Frank E. Koehn*. Med. Chem. Commun., 2012, 3, 854–865
Natural product leads are frequently optimized though structural modification to achieve the final candidate. Of the 58 NP drugs launched in the period 1981–2011, 31 are structural analogues of the native natural product lead (see Supplemental Materials). Since year 2000, 12 of 15 natural product derived drugs are semisynthetic structural analogues, with the exception of Mylotarg and Adcetris, which are antibody drug conjugates. Specific examples in this group are the anti-infective peptides launched in the past 10 years- caspofungin and daptomycin are native natural products while micafungin and anidulafungin are semisynthetic analogues of caspofungin. Televancin is a semi-synthetic analogue of vancomycin. In the polyketide macrolide class, temsirolimus, everolimus and zotarolimus are each semi-synthetic analogues of the natural product rapamycin, and ixabepilone is a semisynthetic analog of epothilone B. Trabectedin (approved by EMEA) was first isolated from a marine tunicate, but is produced semisynthetically from the microbial product cyanosafracin B. Fingolimod and eribulin, both approved in 2010, are fully synthetic analogues of the fungal metabolite myriocin and the sponge metabolite halichondrin B. Carbazitaxel is a semisynthetic derivative of the plant antimitotic paclitaxel. Additional examples can be found in the penem, tetracycline and ketolide classes. Thus, in the recent era, more often than not, natural product Bro5 drugs with the desired combination of potency, safety, and physical properties are the result of modification of the parent molecule.
3. Regioselective enzymatic acylation of complex natural products: expanding molecular diversity
Javier Gonzalez-Sabın,* Roberto Moran-Ramallal* and Francisca Rebolledo*. Chem. Soc. Rev., 2011, 40, 5321–5335
Selective modification of the 42-hydroxyl group of the immunosuppressive and antiproliferative agent rapamycin 5 (Scheme 2) has resulted in the discovery of new derivatives with good activity. One of these, temsirolimus (CCI-779, 7), a 42-ester rapamycin derivative, was approved by the FDA in 2007 as an oncology agent. Gu and co-workers reported the regioselective acylation of 5 at the 42-hydroxyl group using a variety of vinyl esters and anhydrides as acylating agents and different lipases as catalysts. Whereas CAL-B was very efficient when non-hindered vinyl esters and anhydrides were used, Burkholderia cepacia lipase (PSL-C, immobilized on ceramic particles) was efficient with all the vinyl esters tested. Reaction of 5 with the ketal-protected vinyl ester 6 in the presence of PSL-C gave rise to the corresponding ketal ester (98% yield), which was subsequently hydrolyzed to achieve the pharmacologically active temsirolimus 7 (Scheme 2) in nearly quantitative yield. This chemoenzymatic route, which happens without the need for extra protection–deprotection steps, has also been applied for preparing proline-CCI-77914 from prolinerapamycin (a minor component from rapamycin fermentation, the presence of the amino acid proline instead of pipecolic acid being the only structural difference). The proline analogue of 7 is also a useful active drug substance in oncology.
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