Research Interest

A3 receptor targeting novel phototoxic organorutheniums for cancer therapy

For the last three decades anticancer chemotherapy has concentrated on cisplatin derivatives. In spite of their consistent side effects, cisplatin derivates have a central part in most anticancer treatments. In the search for drugs with fewer side effects other metal complexes have been examined over the past few years. Recent research shows that ruthenium complexes have interesting anticancer properties in vivo and they might be a good alternative to platinum-based drugs for anticancer therapy. Ruthenium has numerous properties that qualify it as an antineoplastic drug contender. While platinum-based compounds have served as very successful anti-cancer drugs, they have several limitations including their side effects, as well as ineffectiveness against certain types of cancer. It is thought that some of these issues can be resolved with the use of a ruthenium substitute. Specifically, ruthenium complexes have attracted significant attention with two complexes, namely NAMI-A and KP1019, advancing through clinical trials.

The last compound is active against various primary tumors including those that respond poorly to existing chemotherapy regimens whereas the first displays strong anti-metastatic properties, both with relatively mild side effects. RM-175 is one of the more promising molecules of the ruthenium (II) diamines group. These compounds show high levels of toxicity towards cancer cells, affecting their DNA via a parallel interaction and resulting in apoptosis. ONCO4417 is a very similar molecule, developed by the exchange of a PF6 - anion with the chloride anion found in RM-175. This version of the drug was shown to induce apoptosis as well as halt cell reproduction in cancer types such as ovarian, lung, pancreatic, colorectal, melanoma, and esophageal. It was proven to be effective even in ovarian cancer cases proven to be cisplatin resistant.

The mechanism of action of these ruthenium (III) compounds has been widely studied and it was established that, first, these compounds interact with serum proteins such as albumin and transferring that endows them with tumor seeking properties, second, ruthenium(III) complexes appear to be activated through intracellular reduction to allow generation of toxic ruthenium(II) species, and third, at the tumor site reactions (binding) with proteins are preferred to DNA binding, which contrasts with the behavior of platinum(II) complexes such as cisplatin. Extrapolation of these pathways led to the direct evaluation of ruthenium(II) complexes and, in particular, organometallic ruthenium(II)-arene complexes. Among them, several interesting ruthenium(II) complexes bearing a π-bonded arene ligand has been developed which shows promising anticancer activities, even in cells that had become resistant to cisplatin, such as Sadler’s compounds containing N,N chelating ligands. Besides this, some of the Dyson’s RAPTA compounds containing pta ligand have shown antimetastatic activity. These “piano-stool” geometry containing an arene unit that stabilizes the ruthenium +2 oxidation state and confers hydrophobicity on the global metal complex. Generally, the release of labile chlorido ligands is triggered inside the cell nucleus by the low chloride concentration, allowing for the generation of the activated aqua species that possess the capacity to react with the biological target. Although the mechanism of action of this latter class of compound class remains unclear, it seems likely that RAPTA derivatives have a profoundly different biochemical mode of action to classical platinum anticancer agents. It was shown that in the nucleosome, RAPTA compounds bind preferentially to the histone core relative to the DNA. However, the identification of the full mechanism of action of RAPTA-like molecules still is in progress, as a better mechanistic understanding should help to improve the biological and pharmacological profile of these compounds.

Ruthenium offers several advantages over platinum compounds, including reduced toxicity and the possibility of controlling the shape and the chemical and pharmacological properties of the complex by the adequate selection of the arene and the ligands at the “legs” of the “piano-stool” structure. Moreover, modification of the non-leaving ligands allows the metal complex to be anchored to a “tumor-targeting device” such as receptor-binding peptides, folic acid, or estrogens. This targeted strategy has a tremendous potential in the development of more efficient, less toxic, selective metallodrugs in chemotherapy because receptors for these carrier molecules are overexpressed in the membrane of tumoral cells. Ru-based compounds have attracted increasing attention because the well-known octahedral Ru center provides many synthetic opportunities for tuning the biological activities of inorganic pharmaceuticals by organizing a wide range of ligands in the three-dimensional space.

A3 Adenosine receptor, a G-Protein couple receptor, has been found to be over expressed in some tumor cell lines, such as astrocytoma, B16-F10 and A378 melanoma and HL-60 leukemia, as well as in solid tumors (e.g. 2.3-fold increase in colon carcinomas), and it is correlated with disease progression. Studies have established that this receptor could be a prospective therapeutic target in cancer therapy. Currently, the targeting of A3AR in a clinical setting still presents a major challenge, since modulation of this receptor subtype may induce both pro- or anti-apoptotic effects depending on the duration and the extent of activation/inactivation, as well as on the type of receptor binding. In the past few years, there have been concerted efforts to develop different heterocyclic scaffolds as hA3 ARs antagonists. In our previous study we have developed some pyrazolo pyrimidine based organo ruthenium scaffolds which selectively bind with A3 Adenosine receptor. However, their anticancer properties are still under investigation.

Another strategy to improve efficiency of a metal-based drug is to increase its affinity with its ultimate biological target. The cytotoxicity of ruthenium(II) arene complexes, like that of platinum compounds, has been attributed mainly to the binding of their aquation products to DNA. However, these complexes’ interaction with other potential cellular competitors such as the tripeptide glutathione cannot be ruled out, since they are present in large intracellular concentrations and are responsible for the detoxification of heavier transition metals. In fact, recent studies have revealed that DNA is not always the primary target for some ruthenium anticancer compounds and that they actually bind more strongly to proteins or enzymes than to DNA. Hence, it seems important not only to develop efficient targeting strategies to deliver metallodrugs selectively into cancer cells, but also to direct them toward a particular biological target. RNA offers several advantages over DNA as a drug target, since it is involved in many cellular processes, from the regulation of gene expression to protein synthesis. In recent years, microRNAs (miRNAs) have also emerged as new therapeutic targets for cancer therapy since the abnormal expression of these noncoding small RNAs is associated with the pathogenesis of human cancer.

From these aspects in mind scientists are interested to find out novel organoruthenium drugs for cancer therapy. But the identification of apposite Ruthenium drugs for several biological targets is still a challenge to us. Therefore in our current study we are intend to discover receptor targeting suitable organoruthenium metal drugs for cancer therapy.

Development of novel Fluorescent probes for sub cellular Localization of the drug molecule

We are also interested in developing techniques to study the interactions of these transition

metal-based anticancer drugs with their biological targets. It is often difficult to identify the

target of a particular drug, even ones that have been demonstrated to be highly effective

against cancer cells, due in part due to the complexity of the cellular environment.

Building on established genomics and proteomics methodologies, we are working to develop

new tools that can be applied not only in the identification of drug targets, but also in the

investigation of metal drug-target interactions. Labeling of a small bioactive molecule

with fluorescent probe has been becoming an essential tool in cell biology to reveal the subcellular distribution and the location of molecular target. Here novel fluorescence-tagged chemical probes as bioactive as their parent molecule will be designed and synthesized.

Ruthenium-Iridium based heterodimetallic biotin conjugates and their encapsulated MWCNT form for target delivery and cancer theranostic application

We wish to develop an SMVT targeting heterodimetallic Ru(II)-Ir(III) chemo theranostic DDS in a specific region as well as fluorescence-on, for in vivo and in vitro use. Since biotin demand is more in rapidly proliferating lymphocytes and other malignant cells, the fluorescent heterodimetallic Ru(II)-Ir(III)-biotin conjugates can provide the early diagnosis and treatment for cancers, especially Leukimia and brain cancer. Hence, target specific single system can diagnosis the disease followed by therapy. Therefore, external dyes or attachment of fluorescent nanomaterials with the drug are not required for diagnosis. Here we also wish to modify the surface of MWCNT with biotin followed by fluorescent heterodimetallic Ru(II)-Ir(III) complex is loaded inside the MWCNT via hydrophobic-hydrophobic interaction. The MWCNT-drug will enter in to the cells specifically which has a high fold of biotin expression on their outer cell surface

via receptor mediated endocytosis followed by drug gets release from the MWCNT and their fluorescence was observed. This can help to visualize the bio distribution of the drug in non-invasive manner inside the biological system.

Design, Targeting and PET imaging of D3 Receptor Antagonists as Antipsychotics

Schizophrenia is one of the most debilitating neuropsychiatric disorders, and it affects about 1% of world population. Currently some antipsychotic medicines have discovered which improve psychotic symptoms; however, the disease is complex, being a combination of environmental, genetic and neuro developmental factors. The current medications are primarily based on the “dopamine hypothesis” of psychosis (i.e. a large number of antipsychotics has dopamine antagonistic effects) and there has been accumulating evidence to support the pivotal role of dopamine receptors in schizophrenia. Dopamine, an endogenous neurotransmitter produced in brain which is involved in the pharmacological effects of several antipsychotic drugs. Recently, dopamine D3 receptor antagonists have emerged as a valuable option for the treatment of schizophrenia because dopamine D3 receptor has shown a two-fold over expression in the brain of drug-free hospitalized patients with schizophrenia. However, Dopamine D3 receptors show more restricted and lower expression in the brain compared to D2 receptors. Since D2-like receptors share a highly similar sequence homology with D3 receptor in their transmembrane regions discovery of potent & selective D3 receptor antagonists are still a challenge for drug discovery. To this end, in this project we aim to explore the role of D3 receptors in the treatment of schizophrenia. We are also interested to develop a reliable radiosynthetic method to incorporate 18F isotope into the most promising compounds and perform PET imaging.

Liposomal formulation for effective drug delivery

Fine-tune lipid composition, surface charge, the size.
Cholesterol is included in the bilayers to modify the permeability and stability of the liposome nanoparticles.

Chemically modified with PEG- increase the circulation time in blood stream-improve the transporting capabilities of loaded drugs

Shield the drug from metabolic degradation.

Design, synthesis & formulation of multi targeting chemical entities for the treatment of Parkinson's disease

Parkinson‘s disease (PD), a prevalent neurodegenerative disease in the world with the highest incidence in the aged people. It is associated with the progressive loss of dopamine (DA)-producing neurons in the midbrain, This disease has imposed a significant economic burden on the healthcare budget worldwide, including India & Singapore. Initial endeavors to find therapeutic agents for Parkinson disease followed the “one compound-one target” mindset. Hence in this project we propose to identify new chemical entities that are able to modulate the activity of both A2A and D2 receptors simultaneously (i.e., “one compound-multiple targets” approach). We are also going to develop a liposomal formulation specifically designed to improve the penetration through the blood brain barrier of potent, yet poorly permeable, compounds. The advantages associated with this strategy encompass avoidance of drug-drug interactions, simple pharmacokinetic and pharmacodynamic profiles, more predictable metabolic instabilities and more likely lower side effects.

Mitochondria targeting biotin guided Ir(III) and Re(I) based binuclear complexes for photo-theranostic effects

(i) Re(I)-Ir(III) mixed metallic and Ir(III) bimetallic complexes which will be conjugated with biotin through S-S linkage. (ii) SMVT is overexpressed in cancer cells and hence, biotin will guide the metal conjugates towards cancer cell selectively through endocytosis. (iii) Multinuclear complexes will be selectively accumulated in mitochondria via S-S cleavage (excess GSH will cleave the S-S bond) and exhibit phototoxicity upon irradiation. (iv) High Phosphorescence level of these complexes will assist in tumour diagnosis in the human body.

Emergence of mitochondria targeting Ir(III)/Re(I)based multinuclear complexes as cancer photo-theranostic agent.

The selectivity of themono metallic chemotherapeutic must be improved by using these types of mitochondria specific phototoxic homo and heterobimetallic complexes. Folic acid and biotin guided phototoxic multinuclear complexes will be more effective to minimize the apoptosis in healthy cells. This targeted strategy has an incredible potential in the development of more efficient, less toxic and selective metalodrugs in cancer therapy.

Proposed NIR active phosphorescent molecule is suitable for deep tissue imaging and cancer theranostic application. Since biotin and folic acid demand is more in rapidly proliferating lymphocytes and other malignant cells, the phototoxic phosphorescent homo and heterodimetallic biotin/folic acid conjugates will be delivered selectively in cancer cell and provide the early diagnosis and treatment for cancers, especially Leukimia and brain cancer. Hence, target specific single systems can diagnosis the disease followed by PDT.

A3 receptor targeting novel phototoxic organorutheniums for cancer therapy

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