DOI: 10.1002/cmdc.201100164
Design, Synthesis, and Biological Evaluation of Ring-Opened Bengamide
Analogues
Wan-Yi Tai, Run-Tao Zhang, Yi-Ming Ma, Min Gu, Gang Liu, Jia Li,* and Fa-Jun Nan*[a]
Bengamides are marine natural products, isolated from Jaspi-
dae sponges,[1] that display a wide and interesting range of
biological activities, including antitumor,[2] antibiotic,[3] and an-
thelmintic properties.[1] In particular, their antitumor properties
have stimulated intense research.[4–6] Bengamide B, the most
promising member of this family, and its 5’-ester analogues
were investigated fully by Kinder et al.[4] One analogue,
LAF389, was considered as a clinical candidate, however, poor
pharmacokinetic properties and unclear side effects were ob-
served during the clinical trial.[7] In our previous work, we re-
ported the identification of a new potent analogue, 1o’, which
is N-substituted rather than 5’-substituted, as in the natural
product, and displays more potent activity and greater water
solubility than LAF389 (Figure 1).[6]
Herein, we report a novel series of ring-opened bengamide
analogues obtained by replacing the caprolactam ring with
linear alkyl chains. Among these analogues, several com-
pounds showed potent antitumor activity, as well as good
water solubility (Figure 1). These compounds also present a
novel structure type different from natural bengamides and
allow us to refine the antitumor potency.
A general synthetic procedure for 1–3 is depicted in
Scheme 1. a-Amino acid derivatives 4–6 were prepared by em-
ploying simple and versatile methodologies including esterifi-
Figure 1. The structures of bengamide B, LAF389, and 1o’ and their key bio-
cation and amidation. These derivatives were deprotected and
coupled with lactone 10[8] to obtain ketals 11–13, followed by
logical activities,[4–6] and design strategy for the preparation of ring-opened
bengamide analogues.
removal of the ketal group to give the target compounds 1–3.
Key intermediates 4a–4 f (Scheme 2) were synthesized by
coupling Boc-glycine analogues and compound 14. The latter
was easily prepared from aminoethanol through Boc protec-
tion, esterification and deprotection. Compounds 5a–5k and
6a–6c were prepared from the common intermediate 15a
(Scheme 2). Coupling with various amino alcohols provides in-
termediates 16 and 18a–18c, and further esterification with
various acids or acyl chlorides gave the target compounds.
This study had three key objectives: 1) to simplify the struc-
ture of bengamide analogues and improve their synthetic ac-
cessibility; 2) to identify more potent and water soluble ana-
logues; 3) to further explore the structure–activity relationships
(SAR) of the bengamides. For simplifying the structure of ben-
gamide analogues, the seven-membered ring in 1o’ was
opened, and a series of compounds (1a–1 f) modified at the R1
position were synthesized and evaluated against human breast
carcinoma cells (Table 1). It was found that the simple methyl-
substituted analogue 1a showed high potency, with an IC50
value of 31 nm, while compounds with longer chain lengths
and bulky substituents at this position (1b–1 f) showed lower
potency compared to 1a (Table 1).
Keeping R1 as a methyl group and replacing the cyclohexyl
carboxyl group with a series of alkyl groups, a series of ester
compounds (2a–2k) were synthesized (Table 2). The ester sub-
stituents were selected on the basis of lipophilicity, size, and
shape, and fall into three categories: 1) linear alkyl esters (2a–
2b); 2) branched alkyl esters (2c–2e); and 3) cycloalkyl-substi-
tuted esters (2 f–2k). These analogues were evaluated in the
same bioassay as compounds 1a–1 f, the results of which are
given in Table 2. With a few exceptions, most of these ana-
logues were near equipotent with LAF389. Linear chains (2a
and 2b) gave higher activity than bulky branched esters (2c–
2e). Cycloalkyl esters other than 2j gave high potency with
IC50 values below 31 nm, cyclopentyl-substituted compound 2i
[a] W.-Y. Tai,+ R.-T. Zhang,+ Y.-M. Ma, M. Gu, G. Liu, Dr. J. Li, Prof. Dr. F.-J. Nan
Chinese National Center for Drug Screening, State Key Laboratory of Drug
Research, Shanghai Institute of Materia Medica, Chinese Academy of Scien-
ces, 189 Guoshoujing Road, Zhangjiang Hi-Tech Park, Shanghai, 201203
(People’s Republic of China)
Fax: (+86)21-508-00-954 (FJN)
Fax: (+86)21-508-01-552 (JL)
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW under
ChemMedChem 2011, 6, 1555 – 1558
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1555
Tai, Wan-Yi
