Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl Reactive Pt(II) center as part of redox-active quinoline-based heterocyclic scafolds toward new anticancer leads Sateeshkumar Kumbhakonam a , Soumya Saroj a , Nalini Venkatesan b , Karunagaran Devarajan b , Muraleedharan K. Manheri a, ⁎ a Department of Chemistry, Indian Institute of Technology Madras, Chennai 600036, India b Department of Biotechnology, Indian Institute of Technology Madras, Chennai 600 036, India ARTICLE INFO Keywords: Cisplatin analogs Dihydroquinoline Tetrahydroquinoline Anticancer leads Redox chemotherapy ABSTRACT New cisplatin analogs in which the diamminedichloro-Pt(II) unit is conjugated to dihydroquinoline- or tetra- hydroquinoline frameworks were synthesized and subjected to biological evaluation in order to understand their efects on cellular redox homeostasis and cell viability. They exhibited better selectivity towards cancer cells (A549) compared to mice fbroblast NIH3T3 cells, with cytotoxicity in the same range as that of cisplatin. There was structure-dependent variation in the levels of ROS and were also able to induce cell death, as evidenced by accumulation of cells in sub-G1 phase. Introduction Cisplatin continues to be one of the most potent anticancer drugs in clinical use, and is listed in WHO Model Lists of Essential Medicines. It is used against testicular-, bladder-, ovarian-, cervical-, head & neck-, and esophageal cancers. 1 Ability to form DNA cross-links through N7 of purine bases, mainly from guanine is central to its anti-proliferative action, but lack of selectivity between cancer and normal cells often results in side efects like myelosuppression, immunosuppression, ne- phrotoxicity, hearing loss etc. 2–4 Another bottleneck in cisplatin treat- ment is the drug resistance - both intrinsic and acquired. These happen by way of decreased cellular uptake, increased drug efux, drug deac- tivation by intracellular thiols, and DNA repair by nucleotide excision repair mechanism. 5 Eforts to improve its efcacy have led to the de- velopment of new analogs like carboplatin and oxaliplatin, which are approved worldwide. 6 Other complexes from this class namely neda- platin, lobaplatin and heptaplatin have got approval in Japan, China and Korea, respectively. 1 Common strategies followed to improve the efcacy of Pt(II)-based anticancer agents include i) site-directed drug delivery, 7,8 ii) use of chemical groups to improve the nature and stability of DNA ad- ducts, 9–11 iii) multinuclear Pt-complexes, 12,13 and iv) pro-drugs. 14,15 Use of hybrids such as Ethacraplatin in which individual components formed after bio-activation complement each other’s action is another attractive option. 16 A deeper understanding on the biochemical changes in response to cisplatin will help in the development of new treatment options. Interaction of cisplatin with DNA and other biomolecules like GSH not only afects their individual functions but also has a cascading efect on various metabolic and signaling events. 17,18 Induction of re- sistance also involves various metabolic adaptations, which can be exploited in therapy. 19,20 Elevation of ROS level has been shown as a direct consequence of cisplatin treatment and a cause of apoptosis. 21,22 In fact, cancer cells themselves are characterized by a slightly higher ROS level compared to normal cells because of its involvement in pro- tumorigenic signaling. 23–25 They are however more vulnerable to redox imbalance than normal cells, which is the basis of redox che- motherapy. 26–28 Li et al. have shown the ability of Emodin to increase the chemo- sensitivity of human bladder cancer cells towards cisplatin by in- creasing ROS levels with simultaneous lowering of the expression of multi-resistant related protein MRP1. 29 Similarly, the curcuminoid WZ35 was able to synergistically improve the activity of cisplatin against human gastric cancer cells by increasing ROS level through inhibition of thioredoxin reductase 1 (TrxR1). 30 While redox che- motherapy is promising, elevation of ROS in normal cells could also lead to adverse efects such as nephrotoxicity. 31–33 This shows the ne- cessity to achieve good selectivity as well as spatio-temporal control with the constituents used in the combination. In view of these devel- opments, we envisaged that new cisplatin analogs in which the reactive Pt(II) center is made part of a redox-active chemical scafold will be a good addition to this area. Our group has previously studied the anti- proliferative efects of 1,2-dihydroquinolines (DHQ), and has also https://doi.org/10.1016/j.bmcl.2020.127594 Received 2 June 2020; Received in revised form 3 September 2020; Accepted 26 September 2020 ⁎ Corresponding author. E-mail address: mkm@iitm.ac.in (M.K. Manheri). Bioorganic & Medicinal Chemistry Letters 30 (2020) 127594 Available online 30 September 2020 0960-894X/ © 2020 Elsevier Ltd. All rights reserved. T