FVP of 2-methoxy-N-(arenylidene)anilines gave benzoxazoles¡Fboth FVP and photolysis of 2-thiomethoxy-N-(arenylidene)anilines gave benzothiazoles.

No / Phortress is a novel, potent, and selective experimental antitumor agent. Its mechanism of action involves induction of CYP1A1-catalyzed biotransformation of 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203) to generate electrophilic species, which covalently bind to DNA, exacting lethal damage to sensitive tumor cells, in vitro and in vivo. Herein, we investigate the effects of DNA adduct formation on cellular DNA integrity and progression through cell cycle and examine whether a relevant pharmacodynamic end point may be exploited to probe the clinical mechanism of action of Phortress and predict tumor response. Single cell gel electrophoresis (SCGE) was applied to quantify DNA damage and cell cycle analyses conducted upon 5F 203 treatment of benzothiazole-sensitive MCF-7 and inherently resistant MDA-MB-435 breast carcinoma cells. Following treatment of xenograft-bearing mice and mice possessing hollow fiber implants containing MCF-7 or MDA-MB-435 cells with Phortress (20 mg/kg, i.p., 24 hours), tumor cells and xenografts were recovered for analyses by SCGE. Dose- and time-dependent DNA single and double strand breaks occurred exclusively in sensitive cells following treatment with 5F 203 in vitro (10 nmol/L¿10 ¿mol/L; 24¿72 hours). In vivo, Phortress-sensitive and Phortress-resistant tumor cells were distinct; moreover, DNA damage in xenografts, following treatment of mice with Phortress, could be determined. Interrogation of the mechanism of action of 5F 203 in silico by self-organizing map-based cluster analyses revealed modulation of phosphatases and kinases associated with cell cycle regulation, corroborating observations of selective cell cycle perturbation by 5F 203 in sensitive cells. By conducting SCGE, tumor sensitivity to Phortress, an agent currently undergoing clinical evaluation, may be determined.

Near-infrared (NIR) fluorescence imaging has emerged as an attractive non-invasive approach for direct visualization of diseases which depends on the development of stable, highly specific and sensitive optical probes. The NIR region of the electronic spectrum offers a reduction in the background autofluorescence and an increase in the tissue penetration depth. Cyanine dyes have often been considered promising contrast optic agents owing to their photophysical properties. Herein the synthesis of various penta- and heptamethine benzothiazole cyanine dyes has been described and their in vivo imaging efficacy was determined. Varying functionalities on the benzothiazole aromatic ring and changing substituents on the benzothiazolium nitrogen atom reflected subsequent changes in the imaging pattern and have resulted in the development of promising brain targeting agents.

Near-infrared (NIR) fluorescence imaging has emerged as an attractive non-invasive approach for direct visualization of diseases which depends on the development of stable, highly specific and sensitive optical probes. The NIR region of the electronic spectrum offers a reduction in the background autofluorescence and an increase in the tissue penetration depth. Cyanine dyes have often been considered promising contrast optic agents owing to their photophysical properties. Herein the synthesis of various penta- and heptamethine benzothiazole cyanine dyes has been described and their in vivo imaging efficacy was determined. Varying functionalities on the benzothiazole aromatic ring and changing substituents on the benzothiazolium nitrogen atom reflected subsequent changes in the imaging pattern and have resulted in the development of promising brain targeting agents.

The first chapter describe the pyrolytic and photolytic studies of substituted styrylarenes. Flash vacuum pyrolysis (FVP) of (2-(4-methoxystyryl)-N-methylindole) (18) gave (4-vinylphenol) (81)¡B (7-methyl-7H-benzo[c]carbazole) (82)¡B (benzo[c]carbazole) (83)¡B (1,6-dihydrocyclopenta[c]carbazole) (84) and (3,6-dihydrocyclopenta- [c]carbazole) (84'). FVP of 2',3,5-trimethoxystilbene (31) gave 2-(3,5-dihydroxyphenyl)benzo[b]furan) (26) and 2-(3,5-dimethoxy- phenyl)benzo[b]furan (95). FVP of 2-methoxy-4-(methoxymethyl)-1- [2-(4-methoxyphenyl)-1-methylvinyl]benzene (33) gave [2-(4- methoxyphenyl)-3-methylbenzofuran-5-yl]methanol (104)¡B4-(3,5- dimethylbenzofuran-2-yl)phenol (105) and 2-(4-hydroxyphenyl)-3- methylbenzofuran-5-carbaldehyde (106). FVP of 2-(2-chlorostyryl)- benzo[b]furan (44) ¡B2-(2-chlorostyryl)benzo[b]thiophene (45) and 2-(2-chlorostyryl)-N-methylindole (46) gave benzo[b]naphtha[1,2-d]- furan (116)¡Bbenzo[b]naphtho[1,2-d]thiophene (117)¡B7-methyl-7H- benzo[c] carbazole (82) and benzo[c]carbazole (83). FVP of 2-chloro-N-(N-methylindol-2-ylmethylene)aniline (71) gave N-methylindole-2-carbonitrile (124)¡B 7H-indolo[2,3-c]quinoline (125) and indolo[1,2-a]quinoxaline (126). FVP of 2-methoxy -N-(N-methyl- indol-2-ylmethylene)aniline (72) gave N-methylindole-2-carbonitrile (124) ¡B 2-(N-methylindol- 2-yl)benzoxazole (132) and 2-hydroxy- benzonitrile (133). FVP of 2-methylthio-N-(phenylmethylene)aniline (73)¡B2-methylthio-N-(furylmethylene)aniline (74)¡B2-methylthio-N- (benzo[b]thiophen-2-ylmethylene)aniline (75) and 2-methylthio-N- (N-methylindol-2-ylmethylene)aniline (76) gave 2-phenylbenzothiazole (143)¡B2-furylbenzothiazole (144)¡B2-benzo[b]thiophen-2-ylbenzo- thiazole (145)¡B2-(N-methylindol-2-yl)benzothiazole (146)¡B2-(1H- indol-2-yl)benzothiazole (147) and benzothiazole (148).Such a method, via oxygen-carbon bond disconnecting, can synthesize efficiently a nature product, stemofuran A 26. Photolytic study of 2',3,5-trimethoxystilbene (31) gave 1,5,7- trimethoxyphenanthrene) (101). Photolytic studies of 2-(2-chloro- styryl)benzo[b]furan (44) ¡B2-(2-chlorostyryl)benzo[b]thiophene (45) and 2-(2-chlorostyryl)-N-methylindole (46) gave benzo[b]naphtha- [1,2-d]furan (116) and 4-chlorobenzo[b]naphtha[1,2-d]furan (120)¡Bbenzo[b]naphtho[1,2-d]thiophene (117) and 4-chlorobenzo[b]naphtha- [1,2-d]thiophene (120) ¡B7-methyl-7H- benzo[c]carbazole (82) and 4-chloro-7-methyl-7H-benzo[c]carbazole (121). Photolytic studies of 2-methylthio-N-(phenylmethylene)aniline (73)¡B2-methylthio- -N-(furylmethylene)aniline (74)¡B2-methylthio-N-(benzo[b]thiophen-2- ylmethylene)aniline (75) and 2-methylthio-N-(N-methylindol-2- ylmethylene)aniline (76) gave 2-phenylbenzothiazole (143)¡B2-furyl- benzothiazole (144)¡B2-benzo[b]thiophen-2-ylbenzo- thiazole (145)¡B2-(N-methylindol-2-yl)benzothiazole (146)¡B2-(1H-indol-2-yl)benzo- thiazole (147) and 2-(2,4-dimethoxyphenyl)benzothiazole) (60f). Such a method has the potential for preparing drugs and application on material science. (¤G)FVP of 2-inden-1-ylidenemethylthiophene (24) and 2-inden-1-ylidene- methylfuran (25) gave the cyclized products 2-(2'-thienyl)naphthalene (29) and 2-(2'-furyl)naphthalene (32).

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No / L-type voltage gated calcium channels play essential role in contraction of various skeletal and vascular smooth muscles, thereby plays important role in regulating blood pressure. Dihydropyridine receptors have been targeted for development of newer antihypertensive agents, one of the structurally analogs nucleus dihydropyrimidines have been reported earlier by us as a potential agent toward development of calcium channel modulator. A pre-synthetic QSAR was run and on the basis of structure activity relationship a series of twenty three molecules was synthesized and studied by myosin light chain kinase assay (MLCK), Angiotensin Converting Enzyme (ACE) colorimetric assay, non-invasive blood pressure (NIBP) and invasive blood pressure (IBP) methods. Molecules with significant efficacy were studied for their single crystal X-ray diffraction, molecular docking, molecular dynamics and post-synthetic QSAR. The NIBP and IBP methods screened molecules with better percentage inhibition versus time compared to standard drug Nifedipine. The lead compound ethyl 2-methyl-4-(3-nitrophenyl)-4H-pyrimido [2,1-b] [1,3] benzothiazole-3-carboxylate (26) presented a triclinic structure with polymeric chain packing in lattice. 26 exhibited IC50 on MLCK assay of 2.1+/-1.7 muM with selectivity of L-type calcium channels and comparative to Nifedipine. It offered satisfactory physicochemical properties with partition coefficient of (ClogP) 4.64. Its pharmacokinetic profile is also good with Cmax at 0.40 mug/ml by oral route with Tmax reaching in 0.5 h which means in 30 min. 26 also exhibits superior t1/2 of 5.4 h and oral bioavailability of (F) 56.75% with an AUC0-infinity of 0.84 mug h/ml. Molecular docking studies indicates toward the interaction of lead compound via hydrogen bonds with Lys144, Glu181 and Asp183, it forms the Van der Walls interactions with Ser18, Asp20, Asn187, Pro185, Glu180, Glu181 and Arg10 with Glide score and Glide energy to be -3.602 and -47.098, respectively. Post-synthetic QSAR of newly synthesized molecules indicates toward improvement with respect to steric descriptor which contributed negatively in former series.

Skin pigmentation is an important issue in most cultures. Until recently we have not understood the most important elements of pigmentation regarding detailed chemical structure. The synthesis of melanin is very complex, and although core enzymes, other important proteins, and parts of the melanin structure have been identified much information in this context awaits disclosure. The function of the melanocyte and the deposition of melanin pigments into the keratinocytes are very important in the protection against UV light. Melanin pigments consist of high-molecular structures often described as brown to black eumelanin and yellow to red pheomelanin. Eumelanin is photoprotective, whereas pheomelanin is believed to be carcinogenic after UV radiation. There is strong evidence that people of fair complexion with freckles who tan poorly are at higher risk of developing melanoma. These people have a higher pheomelanin to eumelanin ratio in their skin. Melanoma, one of the most widely spread cancers, is derived from melanocytes. There is accumulating evidence that pigment constitution is highly involved in the development of melanoma. We found that patients with advanced melanoma secrete substantial amounts of pigment structures into the urine, in particular those with diffuse melanosis. In subsequently performed experiments we purified these pigments and subjected the product to chemical degradation by either hydrogen peroxide oxidation or hydriodic hydrolysis. Several new chromatographic methods were developed for the structural analysis of these products. Structural analysis of new chromatographic peaks was performed. In conclusion, complex pheomelanin structures as well as low molecular weight pigments and free benzothiazoles have been identified in the urine of patients with melanoma and diffuse melanosis. The present thesis provides new insight into melanogenesis and melanoma progression. This opens the doorway to further approaches to the investigation of melanins and can help to understand fundamental problems about the structure and biosynthesis of natural melanins.