Photo-physical properties of substituted 2,3-distyryl indoles: Spectroscopic, computational and biological insights.

The structural dependence of the photo-physical properties of substituted 2,3-distyryl (23DSI) indoles were studied using several spectroscopic techniques including steady-state UV-VIS spectroscopy, steady-state fluorescence spectroscopy, steady-state excitation spectroscopy, time correlated single photon counting (TCSPC) spectroscopy, and time-resolved fluorescence upconversion spectroscopy (TRFLS). Each of 23DSI derivatives investigated showed distinct fluorescence emission and UV-VIS spectra, indicating strong structural dependence of the emission and the excitation. The UV-VIS spectra of the 23DSI derivatives showed three main identical absorption bands with minor deviations in the absorbance caused by substituent groups on the distyryl rings. The time-resolved fluorescence up-conversion studies indicated that the fluorescence undergoes a mono-exponential decay whereas the calculated fluorescence lifetime showed relatively short fluorescence lifetimes of approximately 1 ns. All of the 23DSI derivatives showed two-photon absorption upon direct excitation of 1.6 W laser pulses at 800 nm. These studies suggest that the substituents, attached to distyryl core, are capable of boosting or hindering fluorescence intensities by distorting the π-conjugation of the 23DSI molecule. Our studies showed that 23DSI (p-F) has the highest fluorescence emission quantum yield. Theoretical calculations for the ground state of 23DSI derivatives confirmed differences in electron densities in 23DSI derivatives in the presence of different substituent attachments. The excellent fluorescence emission, high fluorescence quantum yield and two-photon absorption properties of these 23DSI molecules make them attractive candidates for potential applications in the fields of biological imaging, biomedicine, fluorescent probes, and photodynamic inactivation (PDI). B. subtilis samples, treated with micro molar solutions of 23DSI (p-OCH3) and 23DSI (p-CH3), showed very effective photodynamic inactivation (PDI) upon irradiation with white light.

Reengineered epipodophyllotoxin.

A variant structural skeleton of epipodophyllotoxin was synthesized and found to rival the natural cyclolignan in antiproliferative and microtubule destabilizing properties. This discovery leads to a new structural class of tubulin targeting agents.

Structural simplification of bioactive natural products with multicomponent synthesis. 4. 4H-pyrano-[2,3-b]naphthoquinones with anticancer activity.

4H-Pyrano-[2,3-b]naphthoquinone is a structural motif commonly found in natural products manifesting anticancer activities. As part of a program aimed at structural simplification of bioactive natural products utilizing multicomponent synthetic processes, we developed a compound library based on this heterocyclic scaffold. We found that several library members displayed low micromolar antiproliferative activity and induced apoptosis in human cancer cells. Selected compounds showed promising activity against cancer cell lines resistant to proapoptotic stimuli, demonstrating their potential in treating cancers with dismal prognoses.

Synthesis of structurally simplified analogues of pancratistatin: truncation of the cyclitol ring.

Pancratistatin is a phenanthridone-type natural product isolated from several plants of the Amaryllidaceae family. Its potent antiproliferative, antivascular, antiviral, and antiparasitic properties have attracted the attention of synthetic, biological, and medicinal chemists. Pancratistatin's low natural availability and complex structure have steered many of these research projects toward the preparation of its simplified synthetic analogues with useful levels of activity. In this work we have developed synthetic chemistry aimed at the preparation of pancratistatin analogues with a truncated cyclitol portion of the molecule. The described synthetic pathways are based on a highly anti-diastereoselective arylcuprate conjugate addition to gamma-alkoxy-alpha,beta-enoates and syn-selective azidation at the alpha-position of ester enolates. Analogues with the formally cleaved C3-C4 bond, and thus containing an open ring C, as well as a compound containing a truncated lactol moiety in lieu of the cyclitol, were prepared. Several of the analogues exhibited weak antiproliferative activity, with the highest potency observed in the case of the lactol analogue. From these results implications for the design of future pancratistatin analogues are discussed. Furthermore, the synthetic pathways can be used to construct pancratistatin-mimetic libraries, in which the cyclitol moiety is replaced by other cyclic motifs.