Morphological characterization of amidinophenylporphyrins interacting with DNA by photo irradiation

5,10,15,20-Tetrakis（4-amidinophenyl）porphyrin（Por 1）,its Zn complex（Por 2）and amidinophenyl bispophyrin（Por 3）interacting with calf thymus DNA were investigated by scanning electron microscopy（SEM）and the shape and size of the porphyrin–DNA complexes were observed after photo irradiation.The results showed that the shape and size of DNA had signifcant differences with blank group by virtue of the interaction between the porphyrins and ct-DNA.This suggests the morphological characterization could be used to study the interaction and judge DNA photocleavage activity indirectly through the photo irradiation of porphyrins.     

Synthesis and biological evaluation of some novel thiadiazole-benzofuran hybrids as potential antitumor agents

Two series of novel 1,3,4-thiadiazole-benzofuran and 1,3,4-thiadiazole-furochromene derivatives were synthesized through heterocyclization of alkyl 2-(1-(6-hydroxy-4,7-dimethoxybenzofuran-5-yl)ethylidene)hydrazine-1-carbodithioate 3a–f and 2-(1-(5-methoxy-8-methyl-2,6-dioxo-2,6-dihydropyrano[3,2-g]chromen-3-yl)ethylidene)hydrazinecarbothioamide 9a,b with various hydrazonoyl halides, respectively. The structure of the newly synthesized products was elucidated through elemental analysis, spectral data and alternative routes whenever possible. Ten new compounds were evaluated for their anticancer activity against the human breast carcinoma (MCF-7) cell lines in comparison with reference doxorubicin using MTT assay. The results showed that some new compounds have promising anticancer activity.     

A novel concept to activate enediynes for DNA cleavage

A novel concept is presented to activate enediynes via a biscumulenic intermediate using photoinduced electron transfer (PET).     

Molecular design and evaluation of quinoxaline-carbohydrate hybrids as novel and efficient photo-induced GG-selective DNA cleaving agents

Quinoxaline, found in antitumor quinoxaline antibiotics, was found to cleave double stranded DNA at the 5' side guanine of 5'-GG-3' site on irradiation with long wavelength UV light without any additive; furthermore, a bis(quinoxaline-carbohydrate) hybrid system was very effective for DNA cleavage.     

Synthesis of lanthanide-based SBA-15 mesoporous hybrids by a novel route

The ligand N², N⁶-bis(2-hydroxyethyl)pyridine-2,6-dicarboxamide (L or BHPC) was synthesised by modification of 2,6-pyridinedicarboxylic acid then used to construct the lanthanide-based mesoporous material Tb-BHPC-SBA-15. In the structure of the resulting Tb-BHPC-SBA-15, lanthanide ions were chelated by the BHPC ligand and the Tb-BHPC complexes were anchored into the SBA-15 host formed by the reaction between the hydroxyl group and the active Si-OH. The mesoporous material Tb-BHPC-SBA-15 was characterised by UV, small-angle X-ray diffraction (SAXRD) patterns, nitrogen adsorption/desorption isotherms and fluorescence spectra. The results indicate that the ligand and lanthanide ions were introduced into the SBA-15 host and the mesoporous material Tb-BHPC-SBA-15 exhibited the characteristic luminescence of Tb³⁺.     

Synthesis and biological evaluation of novel farnesylthiosalicylic acid/salicylic acid hybrids as potential anti-tumor agents

A series of FTS/salicylic acid hybrids was designed and synthesized and their in vitro antitumor activities were evaluated.It was found that the anti-proliferation activities of hybrids were better than that of FTS.Compound 10 a displayed the strongest antitumor activities with IC_(50) values of 5.72-9.76 μmol/L and selectively inhibited tumor cell proliferation.In addition,10 a induced tumor cell apoptosis in a dosedependent manner by up-regulating the expression of Bax and caspase-3 and down-regulating Bcl-2.Our findings suggest that these novel hybrids may hold a great promise as therapeutic agents for the intervention of human cancers.     

DNA cleavage by UVA irradiation of NADH with dioxygen via radical chain processes

Efficient DNA cleaving-activity is observed by UVA irradiation of an O(2)-saturated aqueous solution of NADH (beta-nicotinamide adenine dinucleotide, reduced form). No DNA cleavage has been observed without NADH under otherwise the same experimental conditions. In the presence of NADH, energy transfer from the triplet excited state of NADH ((3)NADH*) to O(2) occurs to produce singlet oxygen ((1)O(2)) that is detected by the phosphorescence emission at 1270 nm. No quenching of (1)O(2) by NADH was observed as indicated by no change in the intensity of phosphorescence emission of (1)O(2) at 1270 nm in the presence of various concentrations of NADH. In addition to the energy transfer, photoinduced electron transfer from (3)NADH* to O(2) occurs to produce NADH(*+) and O(2)(*-), both of which was observed by ESR. The quantum yield of the photochemical oxidation of NADH with O(2) increases linearly with increasing concentration of NADH but decreases with increasing the light intensity absorbed by NADH. Such unusual dependence of the quantum yield on concentration of NADH and the light intensity absorbed by NADH indicates that the photochemical oxidation of NADH with O(2) proceeds via radical chain processes. The O(2)(*-) produced in the photoinduced electron transfer is in the protonation equilibrium with HO(2)(*), which acts as a chain carrier for the radical chain oxidation of NADH with O(2) to produce NAD(+) and H(2)O(2), leading to the DNA cleavage.     

Synthesis and DNA cleavage activity of a novel bleomycin A(5) glycoconjugate

[structure in text] To explore the possibility of modifying bleomycin in a fashion that could alter its physiological distribution in a therapeutic setting, a new analogue of bleomycin has been prepared. This analogue is intended to target the asialoglycoprotein receptor on liver cells. Critically, despite the large C-substituent, the bleomycin conjugate was found to degrade DNA in the same fashion as bleomycin A(5) itself, and with only modestly decreased efficiency.     

Synthesis,pharmacological evaluation,and molecular modeling studies of novel isatin hybrids as potential anticancer agents

A novel series of isatin hybrids 5a-g was designed, synthesized, and characterized spectroscopically. The synthesized compounds were evaluated for their cytotoxic activity against the human breast cancer cell line (MCF-7) by in vitro MTT assay. Amongst the tested compounds, 5e compound bearing benzyl moiety at N₄ piperazine was found to be the most active with the promising IC₅₀ (12.47 µM). Moreover, the active compounds 5e and 5g were subjected to antitumor evaluation (in vivo) against Dalton’s ascitic lymphoma (DAL) cell line and the results suggested that the best active compound 5e can normalize the blood picture in comparison to the standard drug. An in silico molecular docking study using the crystal structure of Hsp90 protein described the role of significant protein–ligand interactions and revealed more insights into the binding mode. The drug-likeliness of the compounds was predicted based on Lipinski's rule of five and pharmacokinetic ADME parameters. Hence, the synthesized isatin hybrids could be novel starting point anticancer lead compounds demonstrating drug-like properties which can be explored further for anticancer drug discovery.     

Synthesis and evaluation of novel caged DNA alkylating agents bearing 3,4-epoxypiperidine structure

Previously, we reported that the 3,4-epoxypiperidine structure, whose design was based on the active site of DNA alkylating antitumor antibiotics, azinomycins A and B, possesses prominent DNA cleavage activity. In this report, novel caged DNA alkylating agents, which were designed to be activated by UV irradiation, were synthesized by the introduction of four photo-labile protecting groups to a 3,4-epoxypiperidine derivative. The DNA cleavage activity and cytotoxicity of the caged DNA alkylating agents were examined under UV irradiation. Four caged DNA alkylating agents showed various degrees of bioactivity depending on the photosensitivity of the protecting groups.     

Evaluation of novel coumarin-proline sulfonamide hybrids as anticancer and antidiabetic agents

Abstract

Cancer and diabetes are considered as two major diseases affecting human health worldwide. Various therapies are available for treatment of cancer and diabetes individually, peptide linkage containing proline sulfonamide can be a promising therapy for treatment of both cancer as well as diabetes. Here, we report design and synthesis of novel coumarin-proline sulfonamide derivatives as anticancer and antidiabetic agents. All the synthesized compounds were screened for their anticancer activity against lungs cancer cell line (A549) and breast cancer cell line (MCF7) using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide dye (MTT)assay and antidiabetic activity using DPP-IV inhibition assay. Compound 16b showed excellent activity against breast cancer cell line (MCF7) with IC₅₀ value of 1.07?µM. All compounds showed moderate DPP-IV inhibition.     

Synthesis and in vitro evaluation of novel tetralin-pyrazolo[3,4-b]pyridine hybrids as potential anticancer agents

New hybrids of tetralin-pyrazolo[3,4-b]pyridine were synthesized in good yields. The structures of newly synthesized compounds were confirmed by IR, NMR, MS, and elemental analyses. Some of the new compounds were in vitro evaluated as antiproliferative candidates against two human cancer cell lines (HCT116 and MCF-7). Most of the examined derivatives showed promising anticancer activity.     

Synthesis of porphobilinogen via a novel ozonide cleavage reaction

Porphobilinogen lactam methyl ester (3a) has been prepared in seven steps, and approximately 20-30% overall yield, beginning with furfurylamine (4a).(24) Hydrolysis of 3a following the literature procedure then gave porphobilinogen (1). A key intermediate in our synthesis of 3a is the 7-oxonorbornene derivative 7a, which was derived from 4a utilizing a tandem Johnson ortho ester Claisen rearrangement followed by intramolecular Diels-Alder cyclization (five steps, 55-65%).(24) Interesting steric accelerating effects were observed in this sequence. Conversion of 7a to 3a was then accomplished employing a novel ozonide cleavage/oxidation reaction, which generated tetrahydrofurans 16a, 32, and 33 in the proper oxidation state for direct aminolysis to pyrrole 3a. A mechanism is proposed for the ozonide cleavage/oxidation that accounts for the observed stereoselectivity of this step.     

Synthesis of novel ferrocene-containing 1,3-thiazinan-2-imines: One-pot reaction promoted by ultrasound irradiation

A simple one-pot synthesis of new ferrocene-containing 1,3-thiazinan-2-imines from 3-arylamino-1-ferrocenylpropan-1-ols and phenyl isothiocyanate has been developed. The key intermediate β-hydroxy thioureas were generated in situ using ultrasound irradiation and subsequent cyclization was achieved by the addition of acetic acid. The scope of the reaction towards various 3-arylamino-1-ferrocenylpropan-1-ols has been explored and the corresponding 3-aryl-6-ferrocenyl-N-phenyl-1,3-thiazinan-2-imines were obtained in moderate to high yields (52–90%).     

DNA cleavage activity of Fe(II)N4Py under photo irradiation in the presence of 1,8-naphthalimide and 9-aminoacridine: unexpected effects of reactive oxygen species scavengers

The DNA cleavage activity of the iron(II) complex of the ligand N,N-bis(2-pyridylmethyl)-N-bis(2-pyridyl)methylamine (N4Py) was investigated in the presence of the chromophores 1,8-naphthalimide (NI) and 9-aminoacridine (AA) under photo irradiation at 355 and 400.8 nm and compared to the activity of the complex without the chromophores. Whereas in most cases no synergistic effect of the added chromophores on DNA cleavage efficiency was observed, it was found that for Fe(II)N4Py, in combination with NI under irradiation at 355 nm, the DNA cleavage activity was increased. Surprisingly, it was found that the addition of reactive oxygen species (ROS) scavengers gave rise to significantly increased DNA cleavage efficiency, which is a highly counterintuitive observation since ROS are needed to achieve DNA cleavage. A hypothesis is put forward to explain, at least partly, these results. It is proposed that the addition of scavengers inhibits quenching of (3)NI*, thus making photo-induced electron transfer between (3)NI* and Fe(III)N4Py more efficient. This results in reduction of Fe(III)N4Py to Fe(II)N4Py, which can then react with ROS giving rise to DNA cleavage. Hence the role of the scavengers is to maintain a close to optimal concentration of ROS. The present study serves as an illustration of the care that needs to be exercised in interpreting the results of experiments using standard ROS scavengers, since especially in complex systems such as presented here they can give rise to unexpected phenomena. In the presence of 1,8-naphthalimide or 9-aminoacridine, ROS scavengers can increase the DNA cleavage efficiency of Fe(II)N4Py complex under photo irradiation.     

Photogeneration of reactive oxygen species and photoinduced plasmid DNA cleavage by novel synthetic chalcones

This paper describes the synthesis and photodynamic properties of six different chalcone derivatives. Using N,N-dimethyl-4-nitrosoaniline (RNO) bleaching assay, the singlet oxygen generating efficiencies of these chalcones are determined relative to rose bengal (RB). Superoxide dismutase (SOD) inhibitable cytochrome c reduction assay and electron magnetic resonance (EMR) spin trapping techniques are used to determine the superoxide anion radical (O?·?) yield upon photoirradiation. Photoinduced DNA scission studies show that O?·? is involved in the DNA strand break. In addition, antimicrobial activity of these chalcones is also investigated. Structure activity relationship accounts for the difference in the photogeneration of reactive oxygen species (ROS) by these sensitizers. Presence of electron releasing -OCH? groups enhances the photogeneration of ROS. Cyclic voltammetry studies indicate a correlation between enzymatic O?·? generation efficiency and redox potential of chalcones. Both O?·? (Type I) and 1O? (Type II) paths are involved in the photosensitization of chalcones. The LUMO energies obtained by molecular modeling correlate with the one-electron reduction potentials.     

Stereoselective synthesis of trans-threo-trans-oligopyrrolidines: potential agents for RNA cleavage

The 2,5-trans-substituted oligopyrrolidines constitute a promising class of novel RNA-binding agents as well as potential building blocks for artificial anion channels. A convergent synthesis of terpyrrolidine 1 and pyrrolidino-THF-pyrrolidine 2 is reported, relying upon convergent coupling of 2,5-trans-pyrrolidinecarboxaldehydes through bridging alkyne units under Felkin-Anh control and subsequent closure of the central ring. After complete deprotection, the free polyamine products were isolated in excellent yield and purity. Crystal structure analyses of a terpyrrolidine and a pyrrolidino-THF-pyrrolidine documented their helical privileged conformations. The compounds were then screened for RNA cleavage activity. Unlike the only weakly active simple polyamines, p-nitrosulfonamide 33 was found to induce cleavage at mM concentrations under physiologically relevant conditions.