Bioorganic & Medicinal Chemistry Letters 12 (2002) 585–587
Synthesis and Antithrombotic Activity of
Carbolinecarboxyl RGD Sequence
Na Lin, Ming Zhao, Chao Wang and Shiqi Peng*
College of Pharmaceutical Sciences, Peking University, Beijing 100083, PR China
Received 9 October 2001; accepted 26 November 2001
Abstract—3S-1,2,3,4-Tetrahydro-b-carboline-3-carboxylic acid, RGDS, RGDV, RGDF and their linkers were synthesized. The
anti-aggregation and adhesion of platelet indicated that the in vitro activities of the linkers remained at the same level as RGDS,
RGDV, and RGDF (p>0.05). The antithrombotic activities in vivo suggested, however, that the potencies of RGDS, RGDV and
RGDF were enhanced by the introduction of 3S-1,2,3,4-tetrahydro-b-carboline-3-carboxyl groupinto their alpha amino group
(p<0.05, 0.01 or 0.001). # 2002 Elsevier Science Ltd. All rights reserved.
In our previous papers, RGDS, RGDV and RGDF
were used as the building blocks in the modification of
the oligopeptides with antithrombotic and/or thrombo-
lytic activity.1,2 The results obtained indicated that the
contribution of RGD sequence to the specific interac-
tion of RGDS, RGDV and RGDF with GP II b/ III a
receptor may result in the targeting ability for RGD-
containing compounds.3.3S-1,2,3,4-Tetrahydro-b-car-
boline-3-carboxylic acid isolated from A.Chinese
G.Don is anti-aggregation active.4 According to the
HPLC analysis, it was understood that RGDS was
degraded by amino peptidase from its N-terminal in the
plasma of animals.5 In the design of the targeting anti-
thrombotic agents, 3S-1,2,3,4-tetrahydro-b-carboline-3-
carboxylic acid was linked with RGDS, RGDV and
RGDF, respectively. By this kind of modification, we
hope that with the targeting action of RGD sequence 3S-
1,2,3,4-tetrahydro-b-carboline-3-carboxylic acid may
distribute to the thrombus forming area and with 3S-
1,2,3,4-tetrahydro-b-carboline-3-carboxylic acid blocking
the N-terminal of RGDS, RGDV and RGDF may inhibit
their amino peptidase based degradation.
phane and formaldehyde gave 3S-1,2,3,4-tetrahydro-b-
carboline-3-carboxylic acid (1)4 in 100% yield. In the
acylation 1 was treated with Boc-N3 and the Boc group
was introduced into the N2 of 1 giving 3S-2-Boc-1,2,3,4-
tetrahydro-b-carboline-3-carboxylic acid (2) in 50%
yield.
The protective tetrapeptide intermediates (3–5) were
prepared via the solution method according to the route
depicted in Scheme 2. The stepwise synthesis (C!N in
83–96% yield) was carried out starting with benzyl ester
of l-Ser (Bzl), l-Val and l-Phe as the C-terminal resi-
due, respectively. Using the normal deprotective proce-
dure 3–5 were treated with HF and 6–8, RGDS (6, in
63% yield), RGDV (7, in 85% yield) and RGDF (8, in
83% yield),3 were obtained. After the removal of Boc
group of protective tetrapeptides 3–5 the corresponding
N-terminal free protective tetrapeptides 9–11 were
obtained in theoretical yield.
Chemistry
The preparation of compounds 1 and 2 was carried out as
outlined in Scheme 1. In the presence of sulfuric acid and
water the Pictet–Spengler condensation of l-trypto-
*Corresponding author. Tel.: +86-10-6209-2482; fax: +86-10-6209-
2311; e-mail: sqpeng@mail.bjmu.edu.cn
Scheme 1. (a) Sulfuric acid; (b) Boc-N3.
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00809-5