Facile synthesis of 1,2-dione-containing abietane analogues for the generation of human carboxylesterase inhibitors

Abstract

Recently, a series of selective human carboxylesterase inhibitors have been identified based upon the tanshinones, with biologically active molecules containing a 1,2-dione group as part of a naphthoquinone core. Unfortunately, the synthesis of such compounds is complex. Here we describe a novel method for the generation of 1,2-dione containing diterpenoids using a unified approach, by which boronic acids are joined to vinyl bromo-cyclohexene derivatives via Suzuki coupling, followed by electrocyclization and oxidation to the o-phenanthroquinones. This has allowed the construction of a panel of miltirone analogues containing an array of substituents (methyl, isopropyl, fluorine, methoxy) which have been used to develop preliminary SAR with the two human carboxylesterase isoforms. As a consequence, we have synthesized highly potent inhibitors of these enzymes (K < 15 nM), that maintain the core tanshinone scaffold. Hence, we have developed a facile and reproducible method for the synthesis of abietane analogues that have resulted in a panel of miltirone derivatives that will be useful tool compounds to assess carboxylesterase biology.

Directionally Modified Fluorophores for Super-Resolution Imaging of Target Enzymes: A Case Study with Carboxylesterases

“…There are two major isoforms of hCEs identified in humans, such as carboxylesterase 1 (hCE1) and carboxylesterase 2 (hCE2). They display a notable difference in tissue distribution and substrate preference. , In addition to modulating lipid/glucose homeostasis, hCEs also participate in the activation of anticancer entities such as irinotecan and gemcitabine. ,,, Current reported inhibitors against hCEs encompass natural compounds like fatty acids, flavonoids, tanshinones, and triterpenoids and synthetic compounds like bisbenzene sulfonamides, 1,2-diones, trifluoroketones, carbamates, etc. Among them, only the 1,2-dione moiety is well-elucidated as the classical functional group through covalently modifying the key serine residue in the catalytic center of hCEs .…”

“…Previously reported studies have confirmed the significance of Ser221 and His468 in the hCE1 reaction, of which the former residue is the nucleophilic attack center toward substrates. ,, We sampled the distribution of key distance involved in the initial hydrolysis reaction. As shown in Figure D, the distance from OSer221 to CLigand (Dis-OSer221_CLigand) corresponding to the nucleophilic attack process has the same distribution pattern for both systems.…”

“…Here, we report the pioneered design of a fluorescent inhibitor for CE and the successful use in structured illumination microscopy (SIM) imaging of CE. On the demand of high specificity toward CE, efforts have been made in data mining of reported substrates and inhibitors of CE, which include naturally occurring molecules and synthetic drug entities targeting and summing up the structure–activity relationship (SAR) of these ligands. − Having found that modification of carbamate would be an important cut-in point, we developed NIC series with the same fluorescent scaffold and modified carbamate configurations (Figure B). Results showed that NIC-4 with methyl substitution of nitrogen in carbamate is an efficient inhibitor for both hCE isoforms.…”

One-Pot Synthesis of 4-Carboalkoxy-Substituted Benzo[h]coumarins from α- and β-Naphthols and Their Excited-State Properties

“…The oxidation of phenols and naphthols by IBX to 1,2-quinones is a well-known reaction . The chemistry of 1,2-quinones has been immensely investigated in the literature .…”

In Silico and In Vitro Identification of P-Glycoprotein Inhibitors from a Library of 375 Phytochemicals

“…Another approach is that miltirone and bidwillon A, as prototypes of natural origin, should be used for chemical modification and structure–activity relationship (SAR) studies to improve its P-gp-inhibiting properties and to drive forward the development of clinical candidates. Miltirone derivatives have been synthesized in the past and subjected to SAR studies in different contexts [ 75 , 76 , 77 ]. These studies may be taken as a proof-of-principle that at least miltirone is in general suitable for derivatization and SAR studies.…”