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Glycosyltransferases constitute a large family of enzymes across all domains of life, but knowledge of their biochemical function remains largely incomplete, particularly in the context of plant specialized metabolism. The labdane diterpenes represent a large class of phytochemicalswithmany pharmacological benefits, such as anti-inflammatory, hepatoprotective, and anticarcinogenic. The medicinal plant kalmegh (Andrographis paniculata) produces bioactive labdane diterpenes; notably, the C19-hydroxyl diterpene (andrograpanin) is predominantly found as C19-Oglucoside (neoandrographolide), whereas diterpenes having additional hydroxylation(s) at C3 (14-deoxy-11,12-didehydroandrographolide) or C3 and C14 (andrographolide) are primarily detected as aglycones, signifying scaffold-selective C19-O-glucosylation of diterpenes in planta. Here, we analyzed UDPglycosyltransferase (UGT) activity and diterpene levels across various developmental stages and tissues and found an apparent correlation ofUGT activity with the spatiotemporal accumulation of neoandrographolide, the major diterpene C19-O-glucoside. The biochemical analysis of recombinant UGTs preferentially expressed in neoandrographolide-accumulating tissues identified a previously uncharacterized UGT86 member (ApUGT12/ UGT86C11) that catalyzes C19-O-glucosylation of diterpenes with strict scaffold selectivity. ApUGT12 localized to the cytoplasm and catalyzed diterpene C19-O-glucosylation in planta. The substrate selectivity demonstrated by the recombinant ApUGT12 expressed inplant and bacteriumhostswas comparable to native UGT activity. Recombinant ApUGT12 showed significantly higher catalytic efficiency using andrograpanin compared with 14-deoxy-11,12-didehydroandrographolide and trivial activity using andrographolide. Moreover, ApUGT12 silencing in plants led to a drastic reduction in neoandrographolide content and increased levels of andrograpanin. These data suggest the involvement of ApUGT12 in scaffold-selective C19-O-glucosylation of labdane diterpenes in plants. This knowledge of UGT86 functionmight help in developing plant chemotypes and synthesis of pharmacologically relevant diterpenes. [ABSTRACT FROM AUTHOR]

Two cytotoxic ruthenium(II) polypyridyl complexes containing naproxen (nap) as NSAID, [Ru(NN) 2 (nap)][PF 6 ] (NN = bpy (1), phen (2)) were synthesized and characterized. The physicochemical properties, theoretical aspects, binding interactions with DNA and BSA and antioxidant activities were investigated. The non-steroidal anti-inflammatory drug (NSAID) naproxen (nap) bound to ruthenium(II) in the presence of a bidentate nitrogen donor heterocyclic ligands (bpy = 2,2′-bipyridine and phen = 1,10-phenanthroline), namely, [Ru(bpy) 2 (nap)][PF 6 ] (1) and [Ru(phen) 2 (nap)][PF 6 ] (2) have been synthesized and characterized using various physicochemical methods. Naproxen was coordinated to the Ru(II) center through carboxylato oxygen atoms (–COO−) in a bidentate fashion. The compounds were evaluated for their photophysical properties, stability in solution, reactivity with 5′-guanosine monophosphate (5′-GMP) and GSH, interactions with CT-DNA and BSA. The complexes showed high binding affinity or reactivity towards these biological targets and bioanalytes. Both the compounds 1 and 2 showed moderate antioxidant activity by scavenging DPPH (1,1-diphenyl-picrylhydrazyl) and ABTS (2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) radicals. The complexes 1 and 2 were highly cytotoxic against PC3 and MCF-7 cancer cells giving IC 50 values ranging from 17 µM to 27 µM. [ABSTRACT FROM AUTHOR]

The effect on the therapeutic efficacy of Pt(II) complexes on combining non-steroidal anti-inflammatory drugs (NSAIDs) is an attractive strategy to circumvent chronic inflammation mediated by cancer and metastasis. Two square-planar platinum(II) complexes: [Pt(dach)(nap)Cl] ( 1 ) and [Pt(dach)(nap) 2 ] ( 2 ), where dach = (1 R ,2 R )-dichloro(cyclohexane-1,2-diamine) and NSAID drug naproxen (nap), have been designed for studying their biological activity. The naproxen bound to the Pt(II) centre get released upon photoirradiation with low-power UV-A light as confirmed by the significant enhancement in emission intensities of the complexes. The compounds were evaluated for their photophysical properties, photostability, reactivity with 5′-guanosine monophophosphate (5′-GMP), interactions with CT-DNA and BSA, antioxidant activity and reactive oxygen species mediated photo-induced DNA damage properties. ESI-MS studies demonstrated the formation of bis-adduct with 5′-GMP and the formation of Pt II -DNA crosslinks by gel electrophoretic mobility shift assay and ITC studies. The interaction of the complexes 1 and 2 with the CT-DNA exhibits potential binding affinity ( K b ∼ 10 4 M −1 , K app ∼ 10 5 M −1 ), implying intercalation to CT-DNA through planar naphthyl ring of the complexes. Both the complexes also exhibit strong binding affinity towards BSA ( K BSA ∼ 10 5 M −1 ). The complexes exhibit efficient DNA damage activity on irradiation at 365 nm via formation of singlet oxygen ( 1 O 2 ) and hydroxyl radical ( • OH) under physiological conditions. Both the complexes were cytotoxic in dark and exhibit significant enhancement of cytotoxicity upon photo-exposure against HeLa and HepG2 cancer cells giving IC 50 values ranging from 8 to 12 μ M for 1 and 2 . The cellular internalization data showed cytosolic and nuclear localization of the complexes in the HeLa cells. [ABSTRACT FROM AUTHOR]