802. Modified steroid hormones. Part XXX. Some 16α,17α-methylenepregnen-20-ones and derived compounds

Burn, D.; Ducker, J.W.; Ellis, B.; Hiscock, A. K.; Leftwick, A. P.; Peach, Catherine M.; Petrow, V.; Williamson, D. M.

doi:10.1039/jr9630004242

Cited by 7 publications

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“…Accordingly, 10 grams of a highly potent anti-inflammatory and cytoprotective agent, (±)-(4bS,8aR,10aS)-10a- 8,4b,7,8,8a,9,10,, was obtained in 15 steps (9.2% overall yield) via the hydroxymethyl tricyclic ketone from 32 grams of cyclohexanone.Tricyclic compound 1 (code number in house, TBE-31, Scheme 1) is the most potent activator of the Keap1/Nrf2/ARE (antioxidant response element) pathway so far. 1 The oral administration of 1 indicated excellent oral bioavailability, and resulted in a dose-dependent induction of cytoprotective enzymes, NAD(P)H:quinone oxidoreductase 1 (NQO1), and glutathione S-transferase (GST) in the stomach, skin, and liver.…”

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An Improved Synthesis of a Hydroxymethyl Tricyclic Ketone from Cyclohexanone, the Key Processes for the Synthesis of a Highly Potent Anti-inflammatory and Cytoprotective Agent

et al. 2013

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An improved synthesis of hydroxymethyl tricyclic ketone, (±)-(4aS,8aS)-8a-(hydroxymethyl)-1, 1,4a-trimethyl-3,4,4a,6,7,8,8a,9,10,10a-decahydrophenanthren-2(1H)-one, in five steps (34% yield) from cyclohexanone has been successfully established. Accordingly, 10 grams of a highly potent anti-inflammatory and cytoprotective agent, (±)-(4bS,8aR,10aS)-10a- 8,4b,7,8,8a,9,10,, was obtained in 15 steps (9.2% overall yield) via the hydroxymethyl tricyclic ketone from 32 grams of cyclohexanone.Tricyclic compound 1 (code number in house, TBE-31, Scheme 1) is the most potent activator of the Keap1/Nrf2/ARE (antioxidant response element) pathway so far. 1 The oral administration of 1 indicated excellent oral bioavailability, and resulted in a dose-dependent induction of cytoprotective enzymes, NAD(P)H:quinone oxidoreductase 1 (NQO1), and glutathione S-transferase (GST) in the stomach, skin, and liver. 2 Furthermore, longterm (five days per week for four weeks) daily topical applications in small quantities (200 nmol) of 1 caused a robust systemic induction of the Keap1/Nrf2/ARE pathway and decreased 6-thioguanine incorporation into DNA of skin, blood, and liver of azathioprine-treated mice, indicating extraordinary bioavailability and efficacy. 3 Tricyclic compound 1 is orally highly active against aflatoxininduced liver cancer in rats. 4 Thus, we envision the preclinical and future clinical studies on 1 as a first in class therapeutic agent for the treatment of inflammation and cancer. For this objective, initially we had to improve the synthesis of hydroxymethyl tricyclic ketone 4c, (±)-(4aS,8aS)-8a-(hydroxymethyl)-1,1,4a-trimethyl-3,4,4a,6,7,8,8a,9,10,10a-decahydrophenanthren-2(1H)-one, from cyclohexanone in order to obtain 10-100 grams of 1. Herein, we report the improved synthesis of 4c from cyclohexanone.We have previously reported the synthesis of 4c from cyclohexanone, but under these processes the reductive methylation step of 3 gives three compounds 4a-c, whose separation requires column chromatography. Moreover, the consequent conversion of 4a and 4b into TBE-31 requires additional steps than that of 4c (Scheme 1). 1,5 Although these three intermediates 4a-c were very useful for the synthesis of various other tricyclic compounds, 6 the previously reported synthesis 1 of 1 could not give a sufficient amount of 1 for preclinical studies. For the efficient synthesis of 1, only intermediate 4c is necessary. Thus we envisioned that, if the new compound 8a can be obtained in a few steps from the previously reported acid 2, which is prepared in two steps from cyclohexanone, 6,7 reductive methylation of 8a would only produce 4c (Scheme 2).Initially we attempted to directly prepare 8a from 2 by selective reduction of the carboxyl group with diborane (strategy A). This method did not give 8a, instead it gave some undesired compounds without UV absorption at 254 nm on TLC. Secondly, we tried to obtain 8a through selective reduction of acyl chloride 5 with reducing agents (strategy B in Scheme 2). Acyl chloride 5 was prepared ...

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confidence: 99%

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confidence: 99%