University of Dundee Diverse amide analogs of sulindac for cancer treatment and prevention

Sulindac is a non-steroidal anti-inflammatory drug (NSAID) that has shown significant anticancer activity. Sulindac sulfide amide (1) possessing greatly reduced COX-related inhibition relative to sulindac displayed in vivo antitumor activity that was comparable to sulindac in a human colon tumor xenograft model. Inspired by these observations, a panel of diverse sulindac amide derivatives have been synthesized and their activity probed against three cancer cell lines (prostate, colon and breast). A neutral analog, compound 79 was identified with comparable potency relative to lead 1 and activity against a panel of lymphoblastic leukemia cell lines. Several new series also show good activity relative to the parent (1), including five analogs that also possess nanomolar inhibitory potencies against acute lymphoblastic leukemia cells. Several new analogs identified may serve as anticancer lead candidates for further development. 2017 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Nonsteroidal anti-inflammatory drugs (NSAIDs) are a chemically diverse family of drugs commonly used clinically to treat a variety of inflammatory conditions including pain associatedwith arthritis. A number of these drugs possess antipyretic activity in addition to having analgesic and anti-inflammatory action, and thus have utility in the treatment of pain and fever. These are widely known to be cyclooxygenase (COX) inhibitors. The COX enzymes participate in the metabolism of prostaglandins. For example, COX-1 enzymes produce prostaglandins that are important for the stomach lining and kidney function. COX-2 enzymes are crucial to anti-inflammatory reactions in the body. Many currently marketed NSAIDs have both COX-1 and COX-2 inhibitory effects. Although the class is highly used both clinically and over the counter, chronic COX inhibition is associated with gastrointestinal, renal, and cardiovascular side effects. Epidemiological, preclinical, and clinical studies suggest that NSAIDs and COX-2 inhibitors display striking cancer chemopreventive efficacy by reducing cancer incidence in the general population. Although the mechanism responsible for the anticancer activity of NSAIDs is still unknown, it is commonly attributed to COX-2mediation. Studies have shown that several human tumors contain increased levels of COX-2 as compared to normal tissues. It has been determined that excess expression of COX-2 in cancer cells correlates to increased tumorigenic potential. Experiments have demonstrated that COX-2 specificNSAIDs restore apoptotic responses, or programmed cell death, in tumor cells. By selective enzyme inhibition and restoration of normal apoptotic responses, research data support the hypothesis that the anti-cancer mechanism is COX-2 dependent. Several COX-2 independent mechanisms have also been postulated for the antineoplastic properties of NSAIDs including activation of apoptosis, inhibition of angiogenesis, or direct inhibition of cancer cell growth by blocking signal transduction pathways responsible for cell proliferation. A number of molecular targets have been implicated in the cyclooxygenase independent pathways of anti-cancer effects of NSAIDs, as reviewed recently, and it was our intention to develop potential probes for these activities through ready variations in the scaffold. Sulindac, or Clinoril, is a substituted indene-3-acetic acid, and is a clinically used NSAID with established chemopreventive activity. Sulindac contains a chiral center (the sulfoxide), although the commercial drug is sold as a racemic mixture. In the body, the drug exists primarily in three active forms (see Fig. 1) due to oxidation-reduction cycling. This cycling scrambles chirality at Fig. 1. In vivo metabolism (oxidation/reduction cycling) of the ASOCH3 center. Scheme 1. Synthetic pathway to analogs 1–86. Reagents: (a) HBTU or HATU, TEA or DIEA, MeCN. B. Mathew et al. / Bioorganic & Medicinal Chemistry Letters 27 (2017) 4614–4621 4615 the SO bond and oxidation to the sulfone is irreversible. The sulfide metabolite generated through bioreduction in vivo is a potent, non-selective COX enzyme inhibitor and shows compelling anticancer activity as compared with other NSAIDS. Based on our and others’ data, it is clear that the NSAIDs have multifarious actions ranging from anti-inflammatory and anti-proliferative effects to selective anticancer cytotoxic activity. The fact that NSAIDs are relatively safe and orally effective suggests that there is an opportunity through simple, specific alterations of the diverse scaffolds to modify the basic structure to probe these various activities, and, at the same time, produce derivations that are more likely to yield good biological probes, animal activity, and drug leads. As an example, the preparation of neutral carboxamides is known to bias the NSAID scaffold towards selective COX2 activity. As well, and supported by our preliminary results that replacement of the carboxylate functionality in sulindac in the form of sulindac sulfide amide (SSA) (1) can virtually abolish COX-related activity and toxicity while potentiating anticancer activity in vitro and yielding in vivo xenograft activity. These results are promising in that sulindac derivatives lacking the carboxylate functionality may show attenuated toxicity (gastric, renal, and cardiovascular) associated with COX inhibition. The presented chemical modifications have begun to explore, and possibly improve on, other NSAID activity space relating to selective cancer prevention and therapy. Herein, we describe the synthesis and anti-cancer activity of a series of sulindac analogs. Compound 1 (SSA) was considered the lead compound, and for this study two modification sites were chosen, the methylthiophenyl ring, and the acetamide linker (Fig. 2). Various aryl groups were introduced in the indene core ring and a series of amides and sulfonamides were synthesized. Fig. 2. Outline of structural modifica All compounds were screened against three cancer cell lines (prostate, colon and breast) and selected compounds against a panel of additional cancer cell lines (five leukemia cancer cell lines and choroid plexus carcinoma cell line).