Targeting genomic DNAs and oligonucleotide on base specificity: A comparative spectroscopic, computational and in vitro study.

Drug discovery in targeted nucleic acid therapeutics encompass several stages and rigorous challenges owing to less specificity of the DNA binders and high failure rate in different stages of clinical trials. In this perspective, we report newly synthesized ethyl 4-(pyrrolo[1,2-a]quinolin-4-yl)benzoate (PQN) with minor groove A-T base pair binding selectivity and encouraging in cell results. This pyrrolo quinolin derivative has shown excellent groove binding ability with three of our inspected genomic DNAs (cpDNA 73 % AT, ctDNA58% AT and mlDNA 28 % AT) with varying A-T and G-C content. Notably in spite of similar binding patterns PQN have strong binding preference with A-T rich groove of genomic cpDNA over the ctDNA and mlDNA. Spectroscopic experiments like steady state absorption and emission results have established the relative binding strengths (Kabs = 6.3 × 105 M-1, 5.6 × 104 M-1, 4.3 × 104 M-1 and Kemiss = 6.1 × 105 M-1, 5.7 × 104 M-1 and 3.5 × 104 M-1 for PQN-cpDNA, PQN-ctDNA and PQN-mlDNA respectively) whereas circular dichroism and thermal melting studies have unveiled the groove binding mechanism. Specific A-T base pair attachment with van der Waals interaction and quantitative hydrogen bonding assessment were characterized by computational modeling. In addition to genomic DNAs, preferential A-T base pair binding in minor groove was also observed with our designed and synthesized deca-nucleotide (primer sequences 5/-GCGAATTCGC-3/ and 3/-CGCTTAAGCG-5/). Cell viability assays (86.13 % in 6.58 µM and 84.01 % in 9.88 µM concentrations) and confocal microscopy revealed low cytotoxicity (IC50 25.86 µM) and efficient perinuclear localization of PQN. We propose PQN with excellent DNA-minor groove binding capacity and intracellular permeation properties, as a lead for further studies encompassing nucleic acid therapeutics.

Tracking the migration of the Indian continent using the carbonate clumped isotope technique on Phanerozoic soil carbonates.

Approximately 140 million years ago, the Indian plate separated from Gondwana and migrated by almost 90° latitude to its current location, forming the Himalayan-Tibetan system. Large discrepancies exist in the rate of migration of Indian plate during Phanerozoic. Here we describe a new approach to paleo-latitudinal reconstruction based on simultaneous determination of carbonate formation temperature and δ(18)O of soil carbonates, constrained by the abundances of (13)C-(18)O bonds in palaeosol carbonates. Assuming that the palaeosol carbonates have a strong relationship with the composition of the meteoric water, δ(18)O carbonate of palaeosol can constrain paleo-latitudinal position. Weighted mean annual rainfall δ(18)O water values measured at several stations across the southern latitudes are used to derive a polynomial equation: δ(18)Ow = -0.006 × (LAT)(2) - 0.294 × (LAT) - 5.29 which is used for latitudinal reconstruction. We use this approach to show the northward migration of the Indian plate from 46.8 ± 5.8°S during the Permian (269 M.y.) to 30 ± 11°S during the Triassic (248 M.y.), 14.7 ± 8.7°S during the early Cretaceous (135 M.y.), and 28 ± 8.8°S during the late Cretaceous (68 M.y.). Soil carbonate δ(18)O provides an alternative method for tracing the latitudinal position of Indian plate in the past and the estimates are consistent with the paleo-magnetic records which document the position of Indian plate prior to 135 ± 3 M.y.

Fe-catalyzed novel domino isomerization/cyclodehydration of substituted 2-[(indoline-3-ylidene)(methyl)]benzaldehyde derivatives: an efficient approach toward benzo[b]carbazole derivatives.

A new and efficient protocol to synthesize substituted benzo[b]carbazole derivatives has been demonstrated involving iron-catalyzed domino isomerization/cyclodehydration sequences from substituted 2-[(indoline-3-ylidene)(methyl)]benzaldehyde derivatives. The substrates could be easily made via Pd-catalyzed domino Heck-Suzuki coupling from 2-bromo-N-propargylanilide derivatives in high yields. Notably, the generality and efficiency of this two-stage domino strategy was further exemplified by the synthesis of a polycyclic benzofuran derivative.

Efficient synthesis of functionalized dihydroquinolines, quinolines and dihydrobenzo[b]azepine via an iron(III) chloride-catalyzed intramolecular alkyne-carbonyl metathesis of alkyne tethered 2-amino benzaldehyde/acetophenone derivatives.

In this study we have developed an efficient synthesis of 1,2-dihydroquinoline and dihydrobenzo[b]azepine derivatives involving the iron(III) chloride intramolecular alkyne-carbonyl metathesis reaction for the first time. Various functionalized 1,2-dihydroquinolines and dihydrobenzo[b]azepines were prepared from easily accessible substrates in the presence of environmentally friendly and inexpensive iron(III) chloride (10 mol%) under mild conditions. The method is applicable to a wide range of substrates containing different functional groups and furnishing products in good to excellent yields. This methodology was further extended to the one-pot synthesis of 3-acyl quinolines via alkyne-carbonyl metathesis/detosylation/aromatization of N-propargyl-2-aminobenzaldehyde/acetophenone derivatives by the addition of NaOH/EtOH. While many Lewis acid and Brønsted acid catalysts were investigated, anhydrous iron(III) chloride turned out to be the best catalyst for this transformation.

FeCl3-catalyzed synthesis of functionally diverse dibenzo[b,f]oxepines and benzo[b]oxepines via alkyne-aldehyde metathesis.

An efficient synthesis of dibenzo[b,f]oxepines and benzo[b]oxepines via FeCl3-catalyzed alkyne-aldehyde metathesis reaction is described. Structurally diverse dibenzo[b,f]oxepines and benzo[b]oxepines have been achieved in good yields with high regio- and chemoselectivity under mild conditions. Notably, among the various catalysts such as Fe(III), Au(III), In(III), Zn(II), Ag(I) and triflic acid, the alkyne-aldehyde metathesis reaction of 2-(2'-phenylethynyl-phenyloxy)-benzaldehyde is only catalyzed by environmentally friendly and sustainable iron(III) chloride.

Synthesis of substituted phenanthrene by iron(III)-catalyzed intramolecular alkyne-carbonyl metathesis.

An efficient synthesis of functionalized phenanthrenes has been developed for the first time involving an iron(III)-catalyzed intramolecular coupling of 2'-alkynyl-biphenyl-2-carbaldehydes. A broad range of functionalized phenanthrene derivatives could be obtained in the present method in moderate to good yields with high chemo- and regioselectivity. This transformation can also be applied to the synthesis of an angularly fused tetracyclic compound. This method offers several advantages such as high selectivity, mild reaction conditions, and easy availability of starting materials.

Iron-catalyzed synthesis of functionalized 2H-chromenes via intramolecular alkyne-carbonyl metathesis.

An iron-catalyzed intramolecular alkyne-aldehyde metathesis strategy of the alkynyl ether of salicylaldehyde derivatives has been developed which works under mild reaction conditions to produce the functionalized 2H-chromene derivatives. This protocol is compatible toward a wide range of functional groups, such as methoxy, fluoro, chloro, bromo, and phenyl groups. This method provides an atom-economical and environmentally friendly approach for the synthesis of a series of substituted 2H-chromenes.