Akhil R Chakravarty’s research while affiliated with Indian Institute of Science Bangalore and other places

Monofunctional Pt(II) complexes [Pt(GL)Cl]Cl (GL–Pt–Cl) and [Pt(RL)Cl]Cl (RL–Pt–Cl), where GL and RL are green and red‐light active PEGylated distyryl BODIPY‐terpyridine moieties, were synthesized and their photo‐ and chemotherapeutic activity studied. BODIPY‐terpyridine ligand was structurally characterized. RL–Pt–Cl showed an intense absorption peak at 658 nm (ε = 9.8 × 10⁴ M⁻¹ cm⁻¹) with a shoulder at ∼624 nm and a broad emission at ∼672 nm in 10% DMSO/DPBS (Dulbecco's Phosphate Buffered Saline). It was produced ¹O2 as evidenced from mechanistic studies. It displayed photocytotoxicity in red light (IC50: 0.7 µM) in MDA‐MB‐231 cells. The 2′,7′‐dichlorofluorescein diacetate assay indicated intracellular generation of reactive oxygen species. It showed chemotherapeutic activity (IC50: 13.7 µM) in A549 cells on 24 h incubation. Pt‐DNA adduct formation was proposed from the 9‐ethylguanine binding experiment. Imaging of RL‐Pt‐Cl treated A549 cancer cells displayed its mitochondrial localization. JC‐1 assay indicated loss of mitochondrial membrane potential in red light. The annexin V‐FITC/propidium iodide assay suggested cellular apoptosis.

Cisplatin‐derived platinum(II) complexes [Pt(NH3)2(pacac)](NO3) (1, DPP‐Pt) and [Pt(NH3)2(Acac‐RB)](NO3) (2, Acacplatin‐RB), where Hpacac is 1,3‐diphenyl‐1,3‐propanedione and HAcac‐RB is a red‐light active distyryl‐BODIPY‐appended acetylacetone ligand, are prepared, characterized and their photodynamic therapy (PDT) activity studied (RB abbreviated for red‐light BODIPY). Complex 2 displayed an intense absorption band at λ=652 nm (ϵ=7.3×10⁴ M⁻¹ cm⁻¹) and 601 nm (ϵ=3.1×10⁴ M⁻¹ cm⁻¹) in 1 : 1 DMSO‐DPBS (Dulbecco's Phosphate Buffered Saline). Its emission profile includes a broad maximum at ~673 nm (λex=630 nm). The fluorescence quantum yield (ΦF) of HAcac‐RB and 2 are 0.19 and 0.07, respectively. Dichlorodihydrofluorescein diacetate and 1,3‐diphenylisobenzofuran assay of complex 2 indicated photogeneration of singlet oxygen (ΦΔ: 0.36) as reactive oxygen species (ROS). Light irradiation caused only minor extent of ligand release forming chemo‐active cisplatin analogue. The complex showed ~70–100 fold enhancement in cytotoxicity on light exposure in A549 lung cancer cells and MDA‐MB‐231 multidrug resistant breast cancer cells, giving half maximal inhibitory concentration (IC50) of 0.9–1.8 μM. Confocal imaging showed its mitochondrial localization and complex 2 exhibited anti‐metastasis properties. Immunostaining of β‐tubulin and Annexin V‐FITC/propidium iodide staining displayed complex 2 induced photo‐selective microtubule rupture and cellular apoptosis, respectively.

Platinum(IV) prodrug, cis , cis , trans -[Pt(NH 3 ) 2 Cl 2 (biotin)( L )] ( 1 ) derived from cisplatin, where H L is PEGylated red-light active boron-dipyrromethene (BODIPY) ligand was synthesized, characterized and its photocytotoxicity evaluated. The complex showed near-IR absorption band at...

To overcome the drawbacks associated with chemotherapeutic and porphyrin-based photodynamic therapy (PDT) agents, the use of BODIPY (boron-dipyrromethene) scaffold has gained prominence in designing a new generation of photosensitizers-cum-cellular imaging agents. However, their poor cell permeability and limited solubility in aqueous medium inhibits the in-vitro application of their organic form. This necessitates the development of metal-BODIPY conjugates with improved physiological stability and enhanced therapeutic efficacy. We have designed two iron(III)-BODIPY conjugates, [Fe(L1/2)(L3)Cl] derived from benzyl-dipicolylamine and its glycosylated analogue along with a BODIPY-tagged catecholate. The complexes showed intense absorption bands (ε ∼ 55,000 M-1 cm-1) and demonstrated apoptotic PDT activity upon red-light irradiation (30 J/cm2, 600-720 nm). The complex with singlet oxygen quantum yield value of ∼0.34 gave sub-micromolar IC50 (half-maximal inhibitory concentration) value (∼0.08 μM) in both HeLa and H1299 cancer cells with a photocytotoxicity index value of >1200. Both the complexes were found to have significantly lower cytotoxic effects in non-cancerous HPL1D (human peripheral lung epithelial) cells. Singlet oxygen was determined to be the prime reactive oxygen species (ROS) responsible for cell damage from pUC19 DNA photo-cleavage studies, 1,3-diphenylisobenzofuran and SOSG (Singlet Oxygen Sensor Green) assays. Cellular imaging studies showed excellent fluorescence from complex 2 within 4 h, with localization in lysosomes. Significant drug accumulation into the core of 3D multicellular tumor spheroids was observed within 8 h from intense in-vitro emission. The complexes exemplify iron-based targeted PDT agents and show promising results as potential transition metal-based drugs for ROS mediated red light photocytotoxicity with low dosage requirement.

A perceived drawback of ruthenium(II) polypyridyl photosensitizers for phototherapeutic applications is their inadequate absorption in the visible region. Ru(II) dyads attached to light‐harvesting organic chromophores are studied to address this issue. Biotin‐appended compounds having one chromophore, namely BODIPY (boron‐dipyrromethene) (1) and Ru(II)‐(tpy)2 (2), or a dyad system containing BODIPY linked to Ru(II)‐(tpy)2 via a diphenylacetylene linker (3) were prepared and studied as photodetection agent and photosensitizes for Photodynamic Therapy (PDT) applications. The bichromophoric 3 with a strong absorption profile (ϵ≈71000 M⁻¹ cm⁻¹ at λmax=503 nm) and high singlet oxygen quantum yield (ΦΔ=0.63 in DMSO) was studied for PDT activity. This complex produced a superoxide anion radical via type‐I and singlet oxygen via type‐II photosensitization processes on light exposure, as evidenced from DNA photo‐cleavage experiments and in vitro DCFDA assay using reactive oxygen species scavengers/quenchers. Dyad 3 displayed an apoptotic photo‐cytotoxic effect against HeLa and H1299 cancer cells with a photocytotoxicity index (PI) value of >625 in HeLa cells with a PDT efficacy much superior to those of its monochromophoric analogs 1 and 2. The intrinsic emission of complex 3, utilized for cellular imaging, showed selectivity towards lysosomes. Finally, the remarkable potential of complex 3 was evidenced using a clinically relevant 3D multicellular tumor spheroid model.