Bioorganic & Medicinal Chemistry Letters 10 (2000) 63±66
Role of the Hydrophobic Moiety of Tumor Promoters.
Synthesis and Activity of 2-Alkylated Benzolactams
Yasuyuki Endo* and Akihiro Yokoyama
Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received 26 September 1999; accepted 18 October 1999
AbstractÐThe size and position of a hydrophobic moiety on a benzolactam skeleton, which reproduces the active conformation
and biological activity of teleocidins, play an important role in the appearance of the activity. Compounds with alkyl groups of
various sizes and shapes at the 2-position of benzolactam were synthesized. Structure±activity results indicate that a hydrophobic
substituent at the C-2 position plays a critical role in the appearance of biological activities, as in the case of substitution at C-9.
# 1999 Elsevier Science Ltd. All rights reserved.
( )-Benzolactam-V8-310 (( )-BL-V8-310, 1)1±3 with an
8-membered lactam ring and a benzene ring instead of
the 9-membered lactam and the indole ring of tumor-
promoting teleocidins (e.g. teleocidin B-4, 2)4, repro-
duces the active ring conformation and biological
activity of teleocidins. The hydrophobic moiety on the
aromatic ring of BL-V8s, as in teleocidins,5,6 plays a
critical role in increasing the biological potency. We
have reported the synthesis and biological activity of 9-
alkylated BL-V8s.7 Among the BL-V8s, substitution of
a C10±C14 linear alkyl chain at the 9-position of the
aromatic nucleus is optimum for the appearance of
biological activity,7 though substitution of a C8±C16
cyclic alkyl group, or even a bulky 1,2-dicarba-closo-
dodecaboran-1-yl group at the 9-position retains almost
the same activity.8 This suggests that the hydrophobic
alkyl group on BL-V8s is folded when the molecule
binds to a receptor. Diterpene ester tumor promoters,
such as 12-O-tetradecanoylphorbol-13-acetate (TPA, 3)
and 3-tetradecanoylingenol (3-TI, 4), which are biologi-
cally identical, have dierent skeletons with hydro-
phobic esters at dierent positions on the molecules.
Thus, it seems likely that a large, oriented hydrophobic
region on the molecule plays a critical role in the
appearance of biological activities. We have designed
and synthesized a benzolactam with a n-decyl group at
the 2-position (BL-8-C10, 5d), which exhibits potent
binding anity to protein kinase Cd (PKCd).9 However,
there is a dierence between the potent Ki value of 5d
toward PKC and its relatively weak EC50 value for HL-
60 dierentiation, so 5d may be useful as a probe for
examination of the mechanism of the biological eects
of binding of TPA-type tumor promoters to PKC.
These results led us to synthesize and biologically
evaluate benzolactams (BLs) bearing alkyl groups of
various sizes and shapes at the 2-position (5b±5l).
Although 2-substituted BL-8s can be synthesized from
racemic 2-(methylamino)phenylalaninol using optically
active tri¯ate of benzyl a-hydroxyalkanoate as a hydro-
phobic component, which is obtained by resolution of
a-aminoalkanoic acid, in a manner similar to that used
for 5d,9 we decided to introduce racemic hydrophobic
components into (S)-N-Boc-2-(methylamino)phenylala-
ninol (6a) followed by diastereomeric separation for
convenience in the preparation of many derivatives.
The key compound 6a was prepared starting from (S)-
phenylalaninol by means of a modi®ed procedure
previously reported.10 The hydrophobic components,
the tri¯ates of the benzyl a-hydroxyalkanoates 7, were
prepared as follows. The appropriate alkanoic acid
ethyl ester 8 (Scheme 1) was converted to the silyl enol
ether, which was oxidized with lead tetraacetate and
treated with HF-pyridine to give the a-acetoxyalkanoic
acid ethyl ester 9 (41±91%).11 Hydrolysis of the two
ester groups of 9 followed by esteri®cation aorded
benzyl a-hydroxyalkanoates 10 (72±94%). Treatment of
10 with tri¯ic anhydride gave the tri¯ate 7 (86±99%).
Reaction of the amine 6a with the tri¯ate 7 gave dia-
stereomeric esters 11 (65±83%). After hydrogenolysis of
the benzyl ester, condensation with N-hydroxy-
succinimide using DCC gave the activated esters 12
*Corresponding author. Tel.: +81-3-5841-4734; fax: +81-3-5841-
4768; e-mail: yendo@mol.f.u-tokyo.ac.jp
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