Phytomedicine 21 (2014) 333–339 Contents lists available at ScienceDirect Phytomedicine jou rn al homepage: www.elsevier.de/phymed Synthesis of novel anticancer iridoid derivatives and their cell cycle arrest and caspase dependent apoptosis Sukanya Pandeti a , Komal Sharma b , Surendar Reddy Bathula b,∗ , Narender Tadigoppula a,∗ a Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226 001, UP, India b Pharmaceutics Division, CSIR-Central Drug Research Institute, Lucknow 226 001, UP, India a r t i c l e i n f o Article history: Received 31 May 2013 Accepted 22 August 2013 Keywords: 7-O-trans-cinnamoyl 6-hydroxyloganin derivatives Arbortristoside-A Anticancer agents Apoptosis Nyctanthes arbortristis a b s t r a c t Nyctanthes arbortristis Linn (Oleaceae) is widely distributed in sub-Himalayan regions and southwards to Godavari, India commonly known as Harsingar and Night Jasmine. In continuation of our drug discovery programme on Indian medicinal plants, we isolated arbortristoside-A (1) and 7-O-trans-cinnamoyl 6- hydroxyloganin (2) from the seeds of N. Arbortristis, which exhibited moderate in vitro anticancer activity. Chemical transformation of 2 led to significant improvement in the activity in derivative 8 and 15 against HepG2 (human hepatocellular carcinoma), MCF-7 (breast adenocarcinoma) cell lines. The compounds 8 and 15 were also capable of cell cycle arrest and caspase dependent apoptosis in HepG2 cell lines. These iridoid derivatives hold promise for developing safer alternatives to the marketed drugs. © 2013 Elsevier GmbH. All rights reserved. Introduction Iridoids represent the group of cyclopentan – (c) – pyran monoterpenoids. They are found as natural constituents in a large number of plant families. Iridoids were first isolated in the lat- ter part of the nineteenth century, but it was not until 1958 that Halpern and Schmid (Halpern et al. 1958) proposed the basic skeleton of the iridoids in their investigation of the structure of plumieride, which possess various biological activities (Chopra et al. 1956). The name iridoid is a generic term derived from the names iridomyrmecin, iridolactone and iridodial compounds iso- lated from some species of Iridomyrmex, a genus of ants, in which they occur as defensive secretions (Roth and Eisner 1962). These compounds have been referred to as pseudoindicans. They have also been referred to as aucubin glucosides. Arbortristoside-A (1) and 7-O-trans-cinnamoyl-6- hydroxyloganin (2) belongs to iridoid class of compounds are the major bioactive compounds of numerous herb species such as Nyctanthes arbortristis Linn (Division: Magnoliophyta; Class: Magnoliopsida; Order: Lamiales; Family: Oleaceae), commonly known as Harsingar and Night Jasmine and possesses leishmanici- dal (Tandon et al. 1991), antiplasmodial (Tuntiwahwuttikul et al. 2003), antispermatogenic (Gupta et al. 2006), antiallergic (Gupta et al. 1995), anti-inflammatory (Amrite et al. 2006; Patel et al. ∗ Corresponding authors. Tel.: +91 522 2612411; fax: +91 522 2623405. E-mail addresses: bsreddy@cdri.res.in (S.R. Bathula), t narendra@cdri.res.in, tnarender@rediffmail.com (N. Tadigoppula). 1998; Saxena et al. 1984; Sanjita Das et al. 2008), antinociceptive (Sanjita Das et al. 2008) and analgesic activity (Saxena et al. 1987). In continuation of our drug discovery programme on anti- cancer agents from Indian medicinal plants, we isolated large quantities of 7-O-trans-cinnamoyl-6-hydroxyloganin (2) from the seeds of Nyctanthes arbortristis Linn and planned to carry out chemical transformation to improve its therapeutic applica- tion. Chemical transformation of bioactive compounds of medicinal herbs is one of the most common approaches in drug discovery to improve the therapeutic properties. For example the anticancer drugs teniposide and etoposide are derivatives of podophyllotoxin and topotecan and irinotecan are analogues of camptothecin, which have better therapeutic benefits than the parent natural prod- ucts. Towards this goal, we have synthesized novel derivatives of compound 2 and evaluated their anticancer activity against HepG2 (human hepatocellular carcinoma), MCF-7 (breast adeno- carcinoma), MDAMB-231 and NIH/3T3 cell lines (Table 1). Further we have studied the apoptosis inducing ability, effect on cell cycle and caspase-3 activation studies of most active compounds 8 and 15. Materials and methods General chemistry IR spectra were recorded on Perkin-Elmer RX-1 spectrometer. Using either KBr pellets (or) in neat. 1 H NMR, 13 C NMR, DEPT-90 and DEPT-135 spectra were run on Bruker Advance DPX 300 MHz and 200 MHz in CDCl 3 . Chemical shifts are reported as values in 0944-7113/$ – see front matter © 2013 Elsevier GmbH. All rights reserved. http://dx.doi.org/10.1016/j.phymed.2013.08.023