Changing Liquid Crystal Helical Pitch with a Reversible Rotaxane Switch.

The transmission of chiral information between the molecular, meso and microscopic scales is a facet of biology that remains challenging to understand mechanistically and to mimic with artificial systems. Here we demonstrate that the dynamic change in the expression of the chirality of a rotaxane can be transduced into a change in pitch of a soft matter system. Shuttling the position of the macrocycle from far-away-from to close-to a point-chiral center on the rotaxane axle changes the expression of the chiral information that is transmitted across length scales; from nanometer scale constitutional chirality that affects the conformation of the macrocycle, to the centimeter scale chirality of the liquid crystal phase, significantly changing the pitch length of the chiral nematic structure.

Synthesis and antiproliferative evaluation of new zampanolide mimics.

(-)-Zampanolide is a marine microtubule-stabilizing macrolide that has been shown by in vitro experiments to be a promising anticancer lead compound. Through its unique covalent-binding with ß-tubulin, zampanolide exhibits cytotoxic potency towards multi-drug resistant cancer cells that is superior to paclitaxel. However, the limited availability of zampanolide impedes its further in vivo evaluation as a viable drug candidate. Zampanolide is envisioned to become more drug-like if its chemically fragile side chain can be stabilized; hence, this project aims to develop mimics of zampanolide with a stable side chain using straightforward synthetic methods. To this end, twelve novel zampanolide mimics (51-62) with conjugated and planar side chains have been synthesized via a 24-step sequence for each mimic from commercially available 2-butyn-1-ol as starting material. A Horner-Wadsworth-Emmons reaction incorporates the α,ß-unsaturated ketone side chain and also closes the core macrocycle. WST-1 cell proliferation assays in three docetaxel-sensitive and two docetaxel-resistant human prostate cancer cell models confirm that a suitably designed side chain can serve as a bioisostere for the N-acyl hemiaminal side chain in zampanolide. Mimic 52 with a 17R chiral center was identified as the optimal candidate with IC50 values of 0.29-0.46 µM against both docetaxel-sensitive (PC-3 and DU145) and docetaxel-resistant prostate cancer cell lines (PC-3/DTX and DU145/DTX). Zampanolide mimic 52 exhibited equivalent antiproliferative potency towards both docetaxel-sensitive and docetaxel-resistant cell lines, with relative resistance in the range of 0.9-1.6.

Immune Modulation of Asian Folk Herbal Medicines and Related Chemical Components for Cancer Management.

Various exciting immunotherapies aiming to address immune deficiency induced by tumor and treatment hold promise in improving the quality of life and survival rate of cancer patients. It is thus becoming an important and rewarding arena to develop some appropriate immune modulators for cancer prevention and/or treatment. Exploitation of natural products-based immune modulators is of particular imperative because the potential of numerous traditional herbal medicines and edible mushrooms in boosting human immune system has long been verified by folklore practices. This review summarizes the immune modulations of various herbal medicines and edible mushrooms, their crude extracts, and/or key chemical components that have been, at least partly, associated with their cancer management. This article also tabulates the origin of species, key chemical components, and clinical studies of these herbal medicines and edible mushrooms.

Optimization of diarylpentadienones as chemotherapeutics for prostate cancer.

Our earlier studies indicate that (1E,4E)-1,5-bis(1-alkyl-1H-imidazol-2-yl)penta-1,4-diene-3-ones and (1E,4E)-1,5-bis(1-alkyl-1H-benzo[d]imidazol-2-yl)penta-1,4-diene-3-ones exhibit up to 121-fold greater antiproliferative potency than curcumin in human prostate cancer cell models, but only 2-10 fold increase in mouse plasma concentrations. The present study aims to further optimize them as anti-prostate cancer agents with both good potency and bioavailability. (1E,4E)-1,5-Bis(1H-imidazol-2-yl)penta-1,4-diene-3-one, the potential metabolic product of (1E,4E)-1,5-bis(1-alkyl-1H-imidazol-2-yl)penta-1,4-diene-3-ones, was synthesized and evaluated for its anti-proliferative activity. The promising potency of 1,5-bis(1-alkyl-1H-imidazol-2-yl)penta-1,4-diene-3-ones was completely abolished by removing the 1-alkyl group, suggesting the critical role of an appropriate group on the N1 position. We then envisioned that N-aryl substitution to exclude the C-H bond on the carbon adjacent to the N1 position (α-H) may increase the metabolic stability. Consequently, seven (1E,4E)-1,5-bis(1-aryl-1H-imidazol-2-yl)penta-1,4-dien-3-ones and three (1E,4E)-1,5-bis(1-aryl-1H-benzo[d]imidazol-2-yl)penta-1,4-dien-3-ones, as well as three (1E,4E)-1,5-bis(1-aryl-1H-pyrrolo[3,2-b]pyridine-2-yl)penta-1,4-dien-3-ones, were synthesized through a three-step transformation, including N-arylation via Ullmann condensation, formylation, and Horner-Wadsworth-Emmons reaction. Six optimal (1E,4E)-1,5-bis(1-aryl-1H-imidazol-2-yl)penta-1,4-dien-3-ones exhibit 24- to 375-fold improved potency as compared with curcumin. Replacement of the imidazole with bulkier benzoimidazole and 4-azaindole results in a substantial decrease in the potency. (1E,4E)-1,5-Bis(1-(2-methoxyphenyl)-1H-imidazol-2-yl)penta-1,4-dien-3-one (17d) was established as an optimal compound with both superior potency and good bioavailability that is sufficient to provide the therapeutic efficacy necessary to suppress in vivo tumor growth.

Optimized synthesis and antiproliferative activity of desTHPdactylolides.

Dactylolide and certain analogues are attractive targets for study due to their structural resemblance to zampanolide, a very promising anticancer lead compound and a unique covalent-binding microtubule stabilizing agent. The primary goal of this project is identification and synthesis of simplified analogues of dactylolide that would be easier to prepare and could be investigated for antiproliferative activity in comparison with zampanolide. Extension of Almann's concept of a simplified zampanolide analogue to dactylolide in the form of desTHPdactylolide was attractive not only for reasons of synthetic simplification but also for the prospect that analogues of dactylolide could be prepared in both (17S) and (17R) configurations. Since Altmann's overall yield for the six-step procedure leading to the C9-C18 fragment of desTHPdactylolide was only 8.7%, a study focused on optimized synthesis and antiproliferative evaluation of each enantiomer of desTHPdactylolide was initiated using Altmann's route as a framework. To this end, two optimized approaches to this fragment C9-C18 were successfully developed by us using allyl iodide or allyl tosylate as the starting material for a critical Williamson ether synthesis. Both (17S) and (17R) desTHPdactylolides were readily synthesized in our laboratory using optimized methods in yields of 37-43%. Antiproliferative activity of the pair of enantiomeric desTHPdactylolides, together with their analogues, was evaluated in three docetaxel-sensitive and two docetaxel-resistant prostate cancer cell models using a WST-1 cell proliferation assay. Surprisingly, (17R) desTHPdactylolide was identified as the eutomer in the prostate cancer cell models. It was found that (17S) and (17R) desTHPdactylolide exhibit equivalent antiproliferative potency towards both docetaxel-sensitive (PC-3 and DU145) and docetaxel-resistant prostate cancer cell lines (PC-3/DTX and DU145/DTX).

Asymmetric 1,5-diarylpenta-1,4-dien-3-ones: Antiproliferative activity in prostate epithelial cell models and pharmacokinetic studies.

To further engineer dienones with optimal combinations of potency and bioavailability, thirty-four asymmetric 1,5-diarylpenta-1,4-dien-3-ones (25-58) have been designed and synthesized for the evaluation of their in vitro anti-proliferative activity in three human prostate cancer cell lines and one non-neoplastic prostate epithelial cell line. All these asymmetric dienones are sufficiently more potent than curcumin and their corresponding symmetric counterparts. The optimal dienone 58, with IC50 values in the range of 0.03-0.12 µM, is 636-, 219-, and 454-fold more potent than curcumin in three prostate cancer cell models. Dienones 28 and 49 emerged as the most promising asymmetric dienones that warrant further preclinical studies. The two lead compounds demonstrated substantially improved potency in cell models and superior bioavailability in rats, while exhibiting no acute toxicity in the animals at the dose of 10 mg/kg. Dienones 28 and 46 can induce PC-3 cell cycle regulation at the G0/G1 phase. However, dienone 28 induces PC-3 cell death in a different way from 46 even though they share the same scaffold, indicating that terminal heteroaromatic rings are critical to the action of mechanism for each specific dienone.