Structure activity relationship study of mezzettiasides natural products and their four new disaccharide analogues for anticancer/antibacterial activity† Sumit O. Bajaj,‡ Pei Shi,‡ Penny J. Beuning * and George A. O'Doherty * Ten members of the mezzettiaside family of natural products were synthesized and evaluated for anticancer and antibacterial activity. Complete anticancer (H460) and antibacterial (B. subtilis) activities for the ten natural products and four new analogues were found. Comparison to the cleistrioside and cleistetroside classes of natural products were made. The mezzettiasides are a family of natural products discovered in 1986 and 1989, 1 as part of the search for the active compo- nent associated with plant extracts from traditional folk medi- cines (Fig. 1). The mezzettiasides 2–11 were isolated from the stem bark of Mezzettia leptopoda, which has been long used in the folk medicinal tradition of the Malaysian island of Borneo. 2 The mezzettiasides are made up of a unique class of partially acetylated oligosaccharides. The carbohydrate core of these octyl di-, tri- and tetrasaccharide natural products consists of an a-linked 1,3-oligorhamnose motif. Because of limited supplies, not all the mezzettiasides were tested for biological activity, however, the ones that showed interesting anticancer activity against a panel of three human cancer cell lines are listed in Table 1. 2 Previously, we have found success with the de novo synthesis 3 and medicinal chemistry study of a related class of carbohydrate based natural products, the cleistriosides and cleistetrosides, 4 using a Pd-catalyzed glycosylation. 5 These studies demonstrated that both the cleistriosides and cleistetrosides possessed both antibacterial and anticancer activity across a range of cell lines (NCI panel of 60 cell lines). 6 While a specic pharmacophore could not be identied, the activity was found to vary upon the length of the carbohydrate chain, as well as the degree and location of acylation. Thus the cleistetrosides were routinely more active than the cleistriosides in anticancer and antibac- terial assays. Access to the mezzettiaside family of natural products allows us to expand the structure activity relationship (SAR) studies, as no biological data were reported for the tet- rasaccharide mezzettiasides 5–7. In addition, we wanted to explore analogues of the simplest disaccharide mezzettiasides 9–11, as these offered the greatest opportunity for structural modication. A review of the reported activities 2 showed a great dependence on the degree of acylation (cf. M-10 to M-11, Table 1), so we decided to make C-3 ester analogues of mez- zettiaside 10. Recently, we reported a divergent de novo asymmetric synthesis of the entire family of the mezzettiaside natural Fig. 1 The targeted mezzettiasides. Table 1 Anticancer cytotoxicity activity (mM) for the mezzettiasides a,2 Cell line b M-2 M-3 M-4 M-8 M-9 M-10 M-11 Lu1 10 14 25 25 9 >20 9 Co12 5 6 8 10 >20 >20 14 KB 7 17 19 >20 19 >20 20 a Results are expressed as ED 50 values (mM). b Lu1 ¼ human lung cancer; Co12 ¼ human colon cancer; KB human oral epidermoid carcinoma; M ¼ mezze. Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA. E-mail: G.ODoherty@neu.edu † Electronic supplementary information (ESI) available: Experimental details, 1 H and 13 C NMR spectra of all synthesized nal products. See DOI: 10.1039/c4md00095a ‡ Co-rst authors, S.O.B. and P.S. are arranged alphabetically. Cite this: Med. Chem. Commun. , 2014, 5, 1138 Received 4th March 2014 Accepted 20th March 2014 DOI: 10.1039/c4md00095a www.rsc.org/medchemcomm 1138 | Med. Chem. Commun., 2014, 5, 1138–1142 This journal is © The Royal Society of Chemistry 2014 MedChemComm CONCISE ARTICLE Published on 21 March 2014. Downloaded by Northeastern University on 03/10/2014 12:17:39. View Article Online View Journal | View Issue