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3
O
O
O
OR
OR
51
OH
OAc
O
O
O
O
O
O
iii
ii
i
OR
OR
OR
OR
97
96
Br
NH
2
i. NBS / benzene, reflux;
ii. Ac
2
O, NaOAc, reflux;
iii. 2N HCl / EtOH, reflux;
iv. Hexamethylenetetramine/
iv, v
O
O
O
O
O
O
OR
OR
OR
OR
CHCl
3
;
v. 2N HCl / EtOH;
iv. Diethylamine / toluene, reflux
98
95
NEt
2
vi
O
O
O
OR
OR
99
Scheme 9-3. Synthetic route to 3-substituted DCK analogs (95-99).
which contains several mutations in RT amino acid residues (M41L, L74V, V106A,
and T215Y) and is resistant to AZT, ddI, nevirapine, and other non-nucleoside
reverse transcriptase inhibitors (NNRTIs).
41
Most previously active DCK deriva-
tives showed dramatically decreased activity or totally lost potency in this new
screening system. It is not fully clear why DCK analogs show remarkably reduced
activity against the drug-resistant viral strains. Mutations of the viral RT could
cause conformational changes directly on the binding sites or other regions that
affect binding. Accordingly, DCK might dissociate more rapidly from or not fit
into the putative mutated target. Therefore, we turned to preparing ring position iso-
mers, a common principle of analog design, as such a change may alter electron
distribution in an aromatic ring system or affect the complimentarity toward in
vivo receptors.
42,43
A series of 3
0
R,4
0
R-di-O-(
)-camphanoyl-2
0
,2
0
-dimethyldihydropyrano[2,3-
f]chromone (DCP, 107) derivatives, which are positional isomers of DCK, were
designed and synthesized.
42,43
All DCP (107-117) and 3
0
-acyl-4
0
-camphanoyl
(118-124) derivatives were tested against both the HIV-1
IIIB
non-drug-resistant
strain in H9 lymphocytes and the HIV-1 RTMDR1 multi-RT inhibitor resistant viral
strain in MT4 cells (Figure 9-6 and Table 9-6). Because the two screening assays
used different protocols, virus strains and cell lines, the activity data cannot be com-
pared between the two different assays. Therefore, our SAR analyses were summar-
ized for each strain.
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