Novel bifunctional acridine-acridinium conjugates: synthesis and study of their chromophore-selective electron-transfer and DNA-binding properties

Novel bifunctional conjugates 1-3, with varying polymethylene spacer groups, were synthesized, and their DNA interactions have been investigated by various biophysical techniques. The absorption spectra of these systems showed bands in the regions of 300-375 and 375-475 nm, corresponding to acridine and acridinium chromophores, respectively. When compared to 1 (Phi(f) = 0.25), bifunctional derivatives 2 and 3 exhibited quantitative fluorescence yields (Phi(f) = 0.91 and 0.98) and long lifetimes (tau = 38.9 and 33.2 ns). The significant quenching of fluorescence and lifetimes observed in the case of 1 is attributed to intramolecular electron transfer from the excited state of the acridine chromophore to the acridinium moiety. DNA-binding studies through spectroscopic investigations, viscosity, and thermal denaturation temperature measurements indicate that these systems interact with DNA preferentially through intercalation of the acridinium chromophore and exhibit significant DNA association constants (K(DNA) = 10(5)-10(7) M(-1)). Compound 1 exhibits chromophore-selective electron-transfer reactions and DNA binding, wherein only the acridinium moiety of 1 interacts with DNA, whereas optical properties of the acridine chromophore remain unperturbed. Among bifunctional derivatives 2 and 3, the former undergoes DNA mono-intercalation, whereas the latter exhibits bis-intercalation; however both of them interact through mono-intercalation at higher ionic strength. Results of these investigations demonstrate that these novel water-soluble systems, which exhibit quantitative fluorescence yields, chromophore-selective electron transfer, and DNA intercalation, can have potential use as probes in biological applications.     

Design of photoactivated DNA oxidizing agents: synthesis and study of photophysical properties and DNA interactions of novel viologen-linked acridines

A new series of photoactivated DNA oxidizing agents in which an acridine moiety is covalently linked to viologen by an alkylidene spacer was synthesized, and their photophysical properties and interactions with DNA, including DNA cleaving properties, were investigated. The fluorescence quantum yields of the viologen-linked acridines were found to be lower than that of the model compound 9-methylacridine (MA). The changes in free energy for the electron transfer reactions were found to be favorable, and the fluorescence quenching observed in these systems is explained by an electron transfer mechanism. Intramolecular electron transfer rate constants were calculated from the observed fluorescence quantum yields and singlet lifetime of MA and are in the range from 1.06x10(10) s(-1) for 1 a (n=1) to 6x10(8) s(-1) for 1 c (n=11), that is, the rate decreases with increasing spacer length. Nanosecond laser flash photolysis of these systems in aqueous solutions showed no transient absorption, but in the presence of guanosine or calf thymus DNA, transient absorption due to the reduced viologen radical cation was observed. Studies on DNA binding demonstrated that the viologen-linked acridines bind effectively to DNA in both intercalative and electrostatic modes. Results of PM2 DNA cleavage studies indicate that, on photoexcitation, these molecules induce DNA damage that is sensitive to formamidopyrimidine DNA glycosylase. These viologen-linked acridines are quite stable in aqueous solutions and oxidize DNA efficiently and hence can be useful as photoactivated DNA-cleaving agents which function purely by the co-sensitization mechanism.     

Tuning the acceptors in catalyzed cyclizations initiated by allenes. Silylstannylation/cyclization of allene-aldehydes for synthesis of polyalkylated indolizidines including 223A congeners

Starting from succinamide and 1,2-heptadiene-4-ol, a racemic allene-aldehyde substrate, 20, suitable for R(3)SiSnR'(3)-mediated cyclization was synthesized in six steps and in 21% yield. Stereoselective cyclization (relative cis configuration at the new stereogenic centers of the homoallyl alcohol generated) proceeded smoothly, giving a mixture of indolizidinols bearing five contiguous stereocenters in a combined yield of 80%. Relative configurations of each of the products were unequivocally established by a combination of 2D NMR experiments and single-crystal X-ray analysis. The major indolizidinol obtained in 32% yield was elaborated into indolizidine 5,8-epi-indolizidine 223A via a five-step reaction sequence in 32% overall yield. The second major component (24%) of the key cyclization yielded, in four steps, indolizidine 6,8-epi-223 in 14% yield. Even though revision of the initially postulated structure foiled our original synthetic plans for the natural product, indolizidine 223A, the new stereoselective cyclization strategy and several selective transformations of the indolizidine derivatives reported here may find further applications for the synthesis of highly alkylated indolizidine and other related alkaloids.     

Generalization of a problem of Evelyn-Linfoot and Page in additive number theory

Summary Let k and l be integers such that 2k l. Let S_k and S _{l l}be two subsets of positive integers with S_kQ_k and S_l Q_l, where Q_k denotes the set of k-free integers. Further suppose that the characteristic functions of S_k and S _{l l} are multiplicative. Let T(n) denote the number of representations of n in the form n=a+b, where a S_k and b S _{l l}. In this paper we establish an asymptotic formula for T(n), when n is sufficiently large; and deduce several known asymptotic formulae as particular cases.     

Selective reduction of anomeric azides to amines with tetrathiomolybdate: synthesis of beta-D-glycosylamines

A number of beta-d-glycosyl azide derivatives undergo reduction on treatment with tetrathiomolybdate to produce the corresponding beta-d-glycosylamines exclusively without anomerization under very mild and neutral reaction conditions. Acetyl, allyl, benzoyl, and benzyl protective groups are left untouched under the reaction conditions. An exclusive selectivity in the reduction of anomeric azides is observed, while the C-2 and C-6 azides are left untouched.     

Synthesis,characterization, in silico and in vitro biological activity studies of Ru(II) (η6-p-cymene) complexes with novel N-dibenzosuberene substituted aroyl selenourea exhibiting Se type coordination

A series of N-dibenzosuberene substituted aroyl selenourea ligands L1–L3 and their Ru(II) (η⁶-p-cymene) complexes 1–3, [Ru(II) (η⁶-p-cymene) L] (L?=?monodentate aroyl selenourea ligand) were synthesized and characterized. The molecular structures of the ligand L3 and complex 3 were confirmed by single-crystal XRD method. The single-crystal XRD study results revealed that aroyl selenourea ligand coordinates with ruthenium via Se neutral monodentate atom. In vitro DNA interaction studies were investigated by UV–Visible and fluorescence spectroscopic methods which showed that the intercalative mode of binding is in the order of 3?>?2?>?1 with the Ru(II) (η⁶-p-cymene) complexes. The binding affinity of the bovine serum albumin with complexes was calculated using spectroscopic methods. Quantum chemical computations were made using DFT (density functional theory), BL3YP; LANL2DZ basis set in order to determine the frontier molecular orbital parameters and MESP for the newly synthesized complexes. The complexes 1–3 have shown intensive cytotoxicity against the cancer lines HepG-2 and A549 under in vitro conditions. Complex 3 (IC₅₀?=?62 μM) has shown significant cytotoxic activity against HepG-2 compared to cisplatin standard drug. The complexes also examined for their antimicrobial activity. The complex 2 exhibited good activity against B. subtilis (MIC: 13.60 μg/mL), E. coli (MIC: 8.01 μg/mL) and A. flavus (MIC?=?15.60 μg/mL), respectively, compared to reference drugs Streptomycin and Ketoconazole.

     

Effect of Bridging Units on Photophysical and DNA Binding Properties of a Few Cyclophanes

A few novel anthracene-based cyclophanes CP-1 , CP-2 and CP-3 were synthesized and their interactions with DNA were investigated employing photophysical and biophysical techniques. In methanol and acetonitrile, these systems exhibited optical properties characteristic of the anthracene chromophore. However, in the aqueous medium, the symmetric cyclophane CP-1 showed a dual emission having λ_max at 430 and 550 nm, due to the monomer and excimer, respectively. In contrast, the cyclophanes CP-2 and CP-3 in the aqueous medium showed structured anthracene absorption and emission spectra similar to those obtained in methanol and acetonitrile. DNA binding studies indicate that CP-1 undergoes efficient nonclassical partial intercalative interactions with DNA resulting in the exclusive formation of a sandwich-type excimer having enhanced emission intensity and lifetimes. The cyclophane CP-2 having one anthracene moiety exhibited nonclassical intercalative binding with DNA, albeit with less efficiency compared with CP-1 . In contrast, CP-3 , having sterically bulky viologen bridging group showed DNA electrostatic as well as groove binding interactions. These results demonstrate that the nature of the bridging unit plays an important role in the binding mode of the cyclophanes with DNA and in the formation of the novel sandwich-type excimer.     

Tuning photosensitized singlet oxygen generation efficiency of novel aza-BODIPY dyes

Novel aza-BODIPY derivatives substituted with heavy atoms such as bromine and iodine were synthesized, and their triplet and singlet oxygen generation efficiencies have been investigated. These derivatives showed absorption in the NIR region with high molar extinction coefficients. The dye substituted with four iodine atoms showed yields of Φ(T) = 0.78 and Φ((1)O(2)) = 0.70, which are the highest values so far obtained for the aza-BODIPY derivatives.