RotM: Interview with Dr. Suresh Thareja & Dr. Sant Kumar Verma

Curcumin analogues as Aldose Reductase Inhibitors for treatment of diabetic complications

For this edition of Researcher of the Month (RotM), we interviewed researchers Dr. Suresh Thareja and research fellow Sant Kumar Verma from Guru Ghasidas Central University located in Bilaspur, Chattisgarh, India. Dr Thareja is the assistant professor for Pharmaceutical Chemistry in the School of Pharmaceutical Sciences at Ghasidas Central University and currently visiting scholar at the Georgia State University, USA. Mr. Sant Kumar Verma is the senior research fellow at the University working on management of diabetic complications. His research is being funded by the Indian Council of Medical Research (ICMR).

Aldose reductase (AR) is an important enzyme since it converts glucose to sorbitol and begins the metabolism of glucose in the body. In patients, with diabetes, the body faces a hyperglycemic condition, which prompts the cells to make high amounts of AR, thereby producing high amounts of sorbitol which is impermeable in the cells and causes osmotic stress. Additionally, AR also requires NADPH as a co factor to function and high amounts of AR utilise large amounts of NADPH making it unavailable for other enzymes and causing oxidative stress. Both these stresses are contribute to complications such as neuropathy, retinopathy and nephropathy that are associated with diabetes. An Aldose reductase Inhibitor (ARI) stops the excess activity of AR and thereby avoids the stresses caused by its activity.

Structure of Aldose reductase enzyme

A recently published paper in PLOS One by the authors we interviewed explores the use of curcumin analogues as drug candidates for development of Aldose reductase (ALR2) inhibitors for management of diabetes mellitus. Curcumin is the common name for diferulolymethane, the principal component of turmeric, which has long been used as a spice and medicinal ingredient in India and China.

CTS: Your recently published research, seems to be the modern scientific result that was needed to show that turmeric could be used as a potential drug to target DM?

Despite advances in the treatment of diabetes, it is still difficult to prevent the development and progression of many of the disabling complications associated with this disease. Among those people with diabetes, the majority of deaths are due to the diabetic complications which include cardiovascular and cerebrovascular diseases, including myocardial ischemia and stroke along with nephropathy, neuropathy, and retinopathy.

Curcumin present in turmeric is a pleiotropic (affecting multiple targets) agent, showing broad range of biological activities. In the present research, we have explored Curcumin for its diabetic complication prevention potential via inhibition of aldose reductase, a molecular level target for the management of diabetic complications.

CTS: What inspired you to work in this direction?

Epalrestat is the single drug molecule available in the market for the treatment of diabetic complication. Other synthetic compounds diffuse poorly in the body. Curcumin, a natural product has been found to possess potent in vitro (in the lab) aldose reductase inhibitory activity. However, due to the presence of β-diketone moiety, it proved to be biologically inactive in a large no. of clinical trials as it undergoes rapid metabolism by the liver enzyme. Therefore, our aim was to develop new molecules using computer aided drug design (CADD) having structural features of Curcumin but having different functionality so that it will remain stable and active when taken by oral route.

CTS: You have mentioned curcuminoids and synthetic curcumin analogues were used in the study. Where are the synthetic curcumin analogues sourced from? What are their applications?

The synthetic curcumin analogues were taken from the literature and we have performed extensive CADD to modify the structural features in order to make it biologically active by improving its bioavailability profile. With CADD, we can predict the biological activity as well as safety parameters of the compounds prior to synthesis/without testing in the animals. Only those compounds will be synthesized in the laboratory which are potent and safe and will be evaluated in animal models.

Aldose Reductase Inhibitors of synthetic (1–5) and natural origin (6) developed during last few decades.Image source: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0175318

CTS: What happens after this? Would your team get involved in a clinical trial to confirm the findings of your study?

Based on the findings of the present study, we will synthesize few active compounds in the laboratory having structural features similar to Curcumin and carry out their preclinical studies in animals for both safety as well as efficacy. Based on the results of preclinical studies, we will protect the active compounds using patent. Further, safe and efficacious molecules will move to clinical studies.

CTS: The paper also mentions that all molecules, except # 8, screened by you have the capability of being an oral drug candidate. Does it also prove that oral intake of turmeric confers benefits to DM patients?

No, as already mentioned above, Curcumin has poor absorption, low bio distribution, fast metabolism, when taken by oral route. Thus, continuous research on curcumin found some possible ways to overcome these problems. Our approach involves use of CADD technique to modify the structure by converting β-diketone moiety to a stable alcoholic form. During this approach, we will make sure that the structure feature of curcumin should remain conserved.

CTS: Traditional Indian cooking also involves, heating of compounds to higher temperatures. Have you already tested or have plans of testing the effect of heat on these analogues and their efficacy?

We will carry out stability studies of the safe active molecules as per ICH guideline in various simulated conditions. These conditions include high temperature, low temperature, light, acid, base and other related factors etc. We will use sophisticated instruments available in the University for determining the structural change in the compound, if any due to these conditions.

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