1. Total Synthesis of (+)-Trachyspic Acid 19- n- Butyl Ester
Alex A Rafaniello, Mark A Rizzacasa Org Lett. 2020 Mar 6;22(5):1972-1975. doi: 10.1021/acs.orglett.0c00319. Epub 2020 Feb 17.
The first total synthesis of the alkyl citrate trachyspic acid 19-n-butyl ester (1) is described. A formal [2 + 2]-cycloaddition of the silylketene acetal derived from lactone 6 with di-n-butylacetylene dicarboxylate 7 provided the cyclobutene diester 5 with a dr >20:1. Acid-mediated rearrangement of 5 followed by lactone ring-opening and ester protecting group manipulation eventually provided orthogonally protected aldehyde 3. A Nozaki-Hiyama-Kishi coupling between 3 and vinyl iodide 4 followed by oxidation of the resultant allylic alcohol gave enone 16, which was converted into the triester 17 (dr 6:1) by a spirocyclization/oxidative cleavage/elimination sequence. Removal of the t-butyl esters then afforded trachyspic acid 19-n-butyl ester (1).
2. Shear Stress and VE-Cadherin
Vincenza Caolo, Hanna M Peacock, Bahar Kasaai, Geertje Swennen, Emma Gordon, Lena Claesson-Welsh, Mark J Post, Peter Verhamme, Elizabeth A V Jones Arterioscler Thromb Vasc Biol. 2018 Sep;38(9):2174-2183. doi: 10.1161/ATVBAHA.118.310823.
Objective- Vascular fusion represents an important mechanism of vessel enlargement during development; however, its significance in postnatal vessel enlargement is still unknown. During fusion, 2 adjoining vessels merge to share 1 larger lumen. The aim of this research was to identify the molecular mechanism responsible for vascular fusion. Approach and Results- We previously showed that both low shear stress and DAPT ( N-[ N-(3,5-difluorophenacetyl)-L-alanyl]- S-phenylglycine t-butyl ester) treatment in the embryo result in a hyperfused vascular plexus and that increasing shear stress levels could prevent DAPT-induced fusion. We, therefore, investigated vascular endothelial-cadherin (VEC) phosphorylation because this is a common downstream target of low shear stress and DAPT treatment. VEC phosphorylation increases after DAPT treatment and decreased shear stress. The increased phosphorylation occurred independent of the cleavage of the Notch intracellular domain. Increasing shear stress rescues hyperfusion by DAPT treatment by causing the association of the phosphatase vascular endothelial-protein tyrosine phosphatase with VEC, counteracting VEC phosphorylation. Finally, Src (proto-oncogene tyrosine-protein kinase Src) inhibition prevents VEC phosphorylation in endothelial cells and can rescue hyperfusion induced by low shear stress and DAPT treatment. Moesin, a VEC target that was previously reported to mediate endothelial cell rearrangement during lumenization, relocalizes to cell membranes in vascular beds undergoing hyperfusion. Conclusions- This study provides the first evidence that VEC phosphorylation, induced by DAPT treatment and low shear stress, is involved in the process of fusion during vascular remodeling.
3. CYP3A4-mediated ester cleavage as the major metabolic pathway of the oral taxane 3'-tert-butyl-3'-N-tert-butyloxycarbonyl-4-deacetyl-3'-dephenyl-3'-N-debenzoyl-4-O-methoxycarbonyl-paclitaxel (BMS-275183)
Donglu Zhang, Van T Ly, Michael Lago, Yuan Tian, Jinping Gan, W Griffith Humphreys, S Nilgün Cömezoglu Drug Metab Dispos. 2009 Apr;37(4):710-8. doi: 10.1124/dmd.108.024398. Epub 2009 Jan 21.
3'-tert-Butyl-3'-N-tert-butyloxycarbonyl-4-deacetyl-3'-dephenyl-3'-N-debenzoyl-4-O-methoxycarbonyl-paclitaxel (BMS-275183) is an orally available taxane analog that has the potential to be used as an oral agent to treat cancers. The compound is similar to the two clinically intravenously administered taxanes, paclitaxel and docetaxel, in that it contains a baccatin ring linked to a side chain through an ester bond. Unlike the other taxanes, the hydrolysis of this ester bond leads to formation of a free baccatin core (M13) that was the major metabolism pathway in incubations of [(14)C]BMS-275183 in human liver microsomes (HLMs) in the presence of NADPH, but it was not formed in incubations with human liver cytosol or HLM in the absence of NADPH. The other prominent metabolites formed in HLM incubations resulted from oxidation of t-butyl groups on the side chain (M20, M20B, M21, M22, and M23). All these metabolites were formed by cDNA-expressed CYP3A and not by other cytochrome P450 (P450) enzymes tested. Formation of these metabolites was selectively inhibited by ketoconazole and troleandomycin. The formation of M13 followed Michaelis-Menten kinetics with the K(m) values of 1.3 to 2.4 muM in HLM or CYP3A4; the V(max) value for the formation of M13 and M23 in the cDNA-expressed CYP3A4 matched well (within 2-fold difference) with that determined in HLM when expressed in units of per picomole of P450. These results showed that BMS-275183 is metabolized by CYP3A4 to yield baccatin through oxidation of side-chain t-butyl groups. An intramolecular cyclization of a side-chain hydroxylation metabolite is proposed to be responsible for the formation of M13, the side-chain hydrolysis metabolite.
