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  • Targeting both PARP and DHODH for anti


    Targeting both PARP-1 and DHODH for anti-cancer therapy would certainly be beneficial as these enzymes share a common role in the DNA replication and repair mechanisms which are involved in the hyper-proliferation of cancer cells. Since benzimidazole-containing compounds have been reported to show good pharmacological activity against these targets,6, 8, 23 we have chosen them as lead structures in the search for dual PARP-1/DHODH inhibitors described in this study.
    Results and discussion
    Conclusion We have studied various benzimidazole derivatives as prospective inhibitors of both PARP-1 and DHODH enzymes. All the compounds have been synthesized in good yields. Several compounds, namely 7f, 10g, 11c and 11f showed dual potencies, albeit with relatively lower activity for both the targets. These compounds, however, can be considered for further study to understand the binding mechanisms and enhance their potential as dual inhibitors of PARP-1 and DHODH.
    Introduction Rapidly growing and dividing cells such as cancer cells require a high amount of pyrimidine to sustain their growth. These cells use the de novo pyrimidine biosynthesis for the synthesis of its DNA and RNA to form a functional gene [1], [2], [3]. In this de novo pathway, dihydroorotate dehydrogenase (DHODH) is a rate limiting enzyme [4], [5], [6] that catalyzes the conversion of dihydroorotate (DHO) to orotate (ORO) present in the mitochondria [7], [8], [9]. Several studies have demonstrated that DHODH could be a potential drug target for cancer therapy, transplant rejection, rheumatoid arthritis, psoriasis and autoimmune diseases [10], [11]. The therapeutic potential of inhibiting DHODH has been demonstrated in the literature using known inhibitors such as leflunomide metabolite, A771726 (LFM), brequinar sodium (BQR) and 4SC-101 [1], [9], [12]. Both LFM and 4SC-101 were developed as potent therapeutic agents for the treatment of autoimmune disorders such as rheumatoid arthritis (RA) [13], [14]. Studies have shown that a metabolite of leflunomide, A771726 induces G1 bcl-2 family arrest in multiple myeloma cells via modulation of cyclin D2 and pRb expression. A771726 also decreases phosphorylation of protein kinase B (Akt), p70S6K, and eukaryotic translation initiation factor 4E-binding protein-1. Brequinar has been documented as a novel anticancer agent that can potentially inhibit growth of a broad spectrum of human solid tumors both in-vitro as well as in in-vivo xenograft models [12], [15], [16]. Brequinar was also reported to act as a modulator of fluorouracil when it was used together in murine colon cancer models [17], [18].
    Materials and methods
    Discussion Hyperactive cell proliferation is a hallmark of cancer which could be due to various internal and external factors. In normal tissues, proliferation rate of cells is generally dependent on their needs. Pyrimidine biosynthesis is fundamental in maintaining the supply of nucleic acids to meet the cellular demand in fast proliferating cells [30]. Normal cells carry out different metabolic activities compared to cancerous cells, in accordance with the cells\' proliferative or differentiation status. This is determined by the mitochondrion which senses the metabolic requirements of those cells [31]. Gene expressions and cellular physiology of normal cells are influenced by growth factors and downstream signalling pathways which allow them to enter cell cycle only when it is necessary thereby limiting autonomous proliferation. For example, the baby hamster kidney (BHK) normal cells have been reported to have an increase in pyrimidine biosynthesis activity by 8-fold when the cells enter exponential growth phase followed by a drop to basal levels as the culture becomes confluent [32]. As the key enzyme in the pyrimidine biosynthesis, DHODH becomes an attractive target for anti-cancer therapy. Although there are several reports on drugs that target DHODH [33], [34], [35], not many have evaluated this enzyme as a therapeutic target for cancer. In this study, we systematically examined, for the first time, the relationship between the expression of DHODH, the speed of cell proliferation and the sensitivity of cells towards three DHODH inhibitors in a wide variety of cancer cells.