K. Nacro et al. / Bioorg. Med. Chem. Lett. 10 (2000) 653±655
655
for PK-C,16±18 the results in Table 1 show, for the ®rst
time, a direct measure of the eect that constraining the
glycerol backbone has on binding anity. The 10-fold
dierence in binding anity between compounds 4 and
9b, which have almost identical log P values, is the
direct result of the entropic advantage of constraining
the glycerol backbone. This dierence could even be
larger if one considers that compound 4 is racemic and
9b is chiral.
11. Marquez, V. E.; Nacro, K.; Benzaria, S.; Lee, J.; Sharma,
R.; Teng, K.; Milne, G. W. A.; Bienfait, B.; Wang, S.; Lewin,
N. E.; Blumberg, P. M. Pharmacol Ther. 1999, 82, 251.
12. Nacro, K.; Bienfait, B.; Lee, J.; Han, K.-C.; Kang, J.-H.;
Benzaria, S.; Lewin, N. E.; Bhattacharyya, D. K.; Blumberg,
P. M.; Marquez, V. E. J. Med. Chem. (in press).
13. Compound 9a: oil; IR (neat) 3508 (OH), 2972 (CH), 1734
1
(CO) cm
;
1H NMR (250 MHz, CDCl3) d 5.15 (m, 1 H,
CHOCO), 4.40 (dd, J=11.9, 3.9 Hz, 1 H, CHHOCO), 4.29
(dd, J=11.9, 5.6 Hz, 1 H, CHHOCO), 3.79 (d, J=5.3 Hz, 2
H, CH2OH), 2.30 (br s, 1 H, OH), 1.28±1.27 (2 s, 18 H,
2ÂC(CH3)3); FAB MS (m/z, relative intensity) 261 (MH+,
21). Anal. calcd for C13H24O5: C, 59.98; H, 9.29. Found: C,
59.98; H, 9.38.
In conclusion, ecient DAG and DAG-lactone ligands
can be constructed provided that they have equivalent,
short acyl chains (branched or unbranched) with ade-
quate lipophilicity. The optimal acyl chain size appears
to be 7 or 8. An additional advantage of having
branched acyl chains may be derived from an increase in
stability toward hydrolysis by esterases, a factor that is
of considerable importance for displaying activity in
whole cells. This was recently shown in the antitumor
screening of comparable DAG-lactones bearing bran-
ched versus linear acyl chains.12
14. Compound 9b: oil; IR (neat) 3472 (OH), 2960 (CH), 1739
1
(CO) cm
;
1H NMR (250 MHz, CDCl3) d 5.15 (m, 1 H,
CHOCO), 4.39 (dd, J=11.9, 4.2 Hz, 1 H, CHHOCO), 4.30
(dd, J=11.9, 5.6 Hz, 1 H, CHHOCO), 3.81 (d, J=5.1 Hz, 2
H, CH2OH), 2.28 (m, 4 H, 2ÂCH2CH(i-Pr)2), 1.81 (m, 4 H,
4ÂCH(CH3)2), 1.70 (m, 2 H, 2ÂCH(i-Pro)2), 0.99±0.97 (2 d,
J=1.9 and 2.2 Hz, 12 H, 2ÂCH(CH3)2), 0.90±0.88 (2 d, J=1.7
Hz, 12 H, 2ÂCH(CH3)2); FAB MS (m/z, relative intensity) 373
(MH+, 15). Anal. calcd for C21H40O5: C, 67.70; H, 10.82.
Found: C, 67.73; H, 10.75.
15. Compound 9c: oil; IR (neat) 3485 (OH), 2912 (CH), 1721
1
(CO) cm
;
1H NMR (250 MHz, CDCl3) d 5.15 (m, 1 H,
References and Notes
CHOCO), 4.37 (dd, J=11.9, 4.3 Hz, 1 H, CHHOCO), 4.24
(dd, J=11.9, 5.9 Hz, 1 H, CHHOCO), 3.76 (d, J=5.1 Hz, 2
H, CH2OH), 2.47 (br s, 1 H, OH), 2.07 (br s, 6 H, CH-ada-
mantyl), 1.95 (br s, 12 H, CH2-adamantyl), 1.75 (m, 12 H,
CH2-adamantyl); FAB MS (m/z, relative intensity) 417
(MH+, 8). Anal. calcd for C25H36O5: C, 72.08; H, 8.71.
Found: C, 71.68; H, 8.84.
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