Azadecalin analogs of 4,4,10β-trimethyl-trans-decal-3β-ol: Synthesis and assay as inhibitors of oxidosqualene cyclase

Structural and Stereoelectronic Requirements for the Inhibition of Mammalian 2,3-Oxidosqualene Cyclase by Substituted Isoquinoline Derivatives

“…Importantly when an aza group was introduced at position 2 in 4,4, 10β-trimethyl- trans -decal-3β-ol (TMD), i . e ., a decalin structure which was previously found to be a cyclase inhibitor, much less inhibition was observed . The same was true for the first generation of isoquinolines …”

“…21 Importantly when an aza group was introduced at position 2 in 4,4,- 10β-trimethyl-trans-decal-3β-ol (TMD), i.e., a decalin structure which was previously found to be a cyclase inhibitor, 22 much less inhibition was observed. 23 The same was true for the first generation of isoquinolines. 21 Mimicking the postulated pro-C-8 intermediary carbocation 2 (Figure 1) by (4aR,5R,6β,8aβ)-decahydro-5,-8a-dimethyl-2-(1,5,9-trimethyldecyl)-6-isoquinolinol (compound 1, Figure 1) led, however, to an efficient cyclase inhibitor.…”

“…The organic layer was washed with brine, dried (MgSO4), and concentrated. The crude material was purified by chromatography with toluene-AcOEt (7:3) to give 2.1 g (50%) of 22 as a yellow solid: mp 84 °C; IR (KBr, 1%) ν (cm -1 ) 1710, 1500, 1460, 750, 700; 1 H NMR (300 MHz, CDCl3) δ 7.30 (m, 5H, Ph), 3.54 (d, J ) 13.1 Hz, H11), 3.47 (d, J ) 13.1 Hz, H11), 2.99 (dm, J ) 10.5 Hz, H3), 2.92 (dm, J ) 10.9 Hz, H1), 2.63 (dt, J ) 6.3, 14.0 Hz, H7), 2.27 (ddd, J ) 2.3, 4.5, 14.0 Hz, H7), 2.00-1.79 (m, H3, H8a, H8), 1.63-1.55 (m, H1, H4, H4), 1.30 (m, H8), 1.09 (m, H4a), 1.07 (s, 3H), 1.05 (s, 3H); 13 (4ar,6β,8aβ)-Decahydro-5,5-dimethyl-2-(phenylmethyl)-6-isoquinolinol (23). Following method F, 23 was obtained starting from 22 as a solid (95%): mp <40 °C; IR (neat) ν (cm -1 ) 3400, 1600, 1470, 1460; 1 H NMR (300 MHz, CDCl3) δ 7.29 (m, 5H, Ph), 3.50 (d, J ) 13.2 Hz, H11), 3.45 (d, J ) 13.2 Hz, H11), 3.23 (dd, J ) 4.2, 11.5 Hz, H6), 2.97 (dm, J ) 11.0 Hz, H3), 2.81 (dm, J ) 8.8 Hz, H1), 1.87 (dt, J ) 2.3, 11.0 Hz, H3), 1.75-1.32 (m, H7, H4, H8a, H1, H7′, H4′, H8, OH), 1.01 (m, H8), 0.96 (s, 3H), 0.77 (s, 3H), 0.68 (m, H4a).…”

Inhibitors of squalene biosynthesis and metabolism

“…However, none was as effective as the known OSC inhibitor, 4,4,10/3-trimethyltrans-decal-3/3-01 (TMD, IC,, = 65 ,UM for rat liver OSC). 145 Vertebrate, yeast, and plant OSCs were all efficiently inhibited by p-chloromercuri benzenesulfonic acid and by N-ethylmaleimide, suggesting the presence of a cysteinyl residue essential for catalysis in the active site of the enzyme.102.106,108 A kinetic studylo2 with partially-purified hog liver OSC gave an apparent K , for N-ethylmaleimide of 2.9 mM and an inactivation constant of 0.089 min-'. Recently, chemical modification of yeast OSC by a new thiol reagent, 3-carboxy-4-nitrophenyl-dithio-1,1',2trisnorsqualene (CNDT-squalene) (273), provided support for the existence of an essential thiol group within the active site of the enzyme.…”

The use of mutants and inhibitors to study sterol biosynthesis in plants

“…Some examples of OSC inhibitors that have been successfully utilized in plants are 2-aza-2,3-dihydrosqualene (5) (Duriatti et al, 1985; Cattel et al, 1986), U18666A (6) (Duriatti et al, 1985; Cattel et al, 1986) and AMO-1618 (7) (Douglas and Paleg, 1978, 1978, 1981). Another class of OSC inhibitors are the 8-azadecalins, such as 4,4,10β-trimethyl-trans-decal-3β-ol (TMD) (8) and its derivatives (Ruhl et al, 1989; Raveendranath et al, 1990; Hoshino et al, 1995). However, the 8-azadecalins also inhibit other enzymes besides OSCs (such as cyclopropyl sterol isomerase, C-14 sterol reductase and C-8,7 sterol isomerase), thus potentially leading to off-target effects.…”