Enantioselective Synthesis of (−)-Dihydrocodeinone: A Short Formal Synthesis of (−)-Morphine^1,^†

The radical cyclization approach to the morphine alkaloids has been applied in an asymmetric synthesis of (−)-dihydrocodeinone. A chiral cyclohexenol (R-32), from the CBS reduction of the enone, is the source of chirality. The first key step, tandem closure in which stereochemistry is controlled by geometric constraints, (−)-15b → (+)-16, was followed by an unprecedented reductive hydroamination, completing the synthesis of (−)-dihydroisocodeine ((−)-17) in 13 steps from commercially available materials

Enantioselective Synthesis of (−)-Dihydrocodeinone: A Short Formal Synthesis of (−)-Morphine^1,^†

The radical cyclization approach to the morphine alkaloids has been applied in an asymmetric synthesis of (−)-dihydrocodeinone. A chiral cyclohexenol (R-32), from the CBS reduction of the enone, is the source of chirality. The first key step, tandem closure in which stereochemistry is controlled by geometric constraints, (−)-15b → (+)-16, was followed by an unprecedented reductive hydroamination, completing the synthesis of (−)-dihydroisocodeine ((−)-17) in 13 steps from commercially available materials

Diversity Oriented Synthesis of a Vinblastine-Templated Library of 7‑Aryl-Octahydroazonino[5,4‑<i>b</i>]indoles via a Three-Component Reaction

A vinblastine-templated library of 7-aryl-octahydroazonino­[5,4-<i>b</i>]­indoles was prepared by a three-component reaction from indolizino­[8,7-<i>b</i>]­indoles, chloroformates, and activated arenes via a chloroformate mediated fragmentation of the indolizinoindole nucleus followed by insertion of an activated arene. In addition to N3-carbamoyl-7-aryl-octahydroazonino­[5,4-<i>b</i>]­indoles prepared in one step, a wide range of N3-substituted substrates were synthesized in one pot via the derivatization of a versatile N3–H-azonino­[5,4-<i>b</i>]­indole intermediate generated in situ by application of the same strategy. A subset of 308 compounds out of a virtual library of 3216, representing 13 different chemotypes, was prepared by high throughput solution-phase synthesis and subsequently purified by mass-triggered high performance liquid chromatography (HPLC). A total of 188 compounds with a minimum purity of 80% by UV_214 nm and 85% by evaporative light scattering detection (ELSD) was isolated for primary screening

Diversity Oriented Synthesis of a Vinblastine-Templated Library of 7‑Aryl-Octahydroazonino[5,4‑<i>b</i>]indoles via a Three-Component Reaction

A vinblastine-templated library of 7-aryl-octahydroazonino­[5,4-<i>b</i>]­indoles was prepared by a three-component reaction from indolizino­[8,7-<i>b</i>]­indoles, chloroformates, and activated arenes via a chloroformate mediated fragmentation of the indolizinoindole nucleus followed by insertion of an activated arene. In addition to N3-carbamoyl-7-aryl-octahydroazonino­[5,4-<i>b</i>]­indoles prepared in one step, a wide range of N3-substituted substrates were synthesized in one pot via the derivatization of a versatile N3–H-azonino­[5,4-<i>b</i>]­indole intermediate generated in situ by application of the same strategy. A subset of 308 compounds out of a virtual library of 3216, representing 13 different chemotypes, was prepared by high throughput solution-phase synthesis and subsequently purified by mass-triggered high performance liquid chromatography (HPLC). A total of 188 compounds with a minimum purity of 80% by UV_214 nm and 85% by evaporative light scattering detection (ELSD) was isolated for primary screening

Diversity Oriented Synthesis of a Vinblastine-Templated Library of 7‑Aryl-Octahydroazonino[5,4‑<i>b</i>]indoles via a Three-Component Reaction

A vinblastine-templated library of 7-aryl-octahydroazonino­[5,4-<i>b</i>]­indoles was prepared by a three-component reaction from indolizino­[8,7-<i>b</i>]­indoles, chloroformates, and activated arenes via a chloroformate mediated fragmentation of the indolizinoindole nucleus followed by insertion of an activated arene. In addition to N3-carbamoyl-7-aryl-octahydroazonino­[5,4-<i>b</i>]­indoles prepared in one step, a wide range of N3-substituted substrates were synthesized in one pot via the derivatization of a versatile N3–H-azonino­[5,4-<i>b</i>]­indole intermediate generated in situ by application of the same strategy. A subset of 308 compounds out of a virtual library of 3216, representing 13 different chemotypes, was prepared by high throughput solution-phase synthesis and subsequently purified by mass-triggered high performance liquid chromatography (HPLC). A total of 188 compounds with a minimum purity of 80% by UV_214 nm and 85% by evaporative light scattering detection (ELSD) was isolated for primary screening

Gemcitabine Based Peptide Conjugate with Improved Metabolic Properties and Dual Mode of Efficacy

Gemcitabine is a clinically established anticancer agent potent in various solid tumors but limited by its rapid metabolic inactivation and off-target toxicity. We have previously generated a metabolically superior to gemcitabine molecule (GSG) by conjugating gemcitabine to a gonadotropin releasing hormone receptor (GnRH-R) ligand peptide and showed that GSG was efficacious in a castration resistant prostate cancer (CRPC) animal model. The current article provides an in-depth metabolic and mechanistic study of GSG, coupled with toxicity assays that strengthen the potential role of GSG in the clinic. LC–MS/MS based approaches were employed to delineate the metabolism of GSG, its mechanistic cellular uptake, and release of gemcitabine and to quantitate the intracellular levels of gemcitabine and its metabolites (active dFdCTP and inactive dFdU) resulting from GSG. The GnRH-R agonistic potential of GSG was investigated by quantifying the testosterone levels in animals dosed daily with GSG, while an <i>in vitro</i> colony forming assay together with <i>in vivo</i> whole blood measurements were performed to elucidate the hematotoxicity profile of GSG. Stability showed that the major metabolite of GSG is a more stable nonapeptide that could prolong gemcitabine’s bioavailability. GSG acted as a prodrug and offered a metabolic advantage compared to gemcitabine by generating higher and steadier levels of dFdCTP/dFdU ratio, while intracellular release of gemcitabine from GSG in DU145 CRPC cells depended on nucleoside transporters. Daily administrations in mice showed that GSG is a potent GnRH-R agonist that can also cause testosterone ablation without any observed hematotoxicity. In summary, GSG could offer a powerful and unique pharmacological approach to prostate cancer treatment: a single nontoxic molecule that can be used to reach the tumor site selectively with superior to gemcitabine metabolism, biodistribution, and safety while also agonistically ablating testosterone levels

Grafting of Imidazolium Based Ionic Liquid on the Pore Surface of Nanoporous MaterialsStudy of Physicochemical and Thermodynamic Properties

Supported ionic liquid phase (SILP) systems were prepared by immobilizing a methylimidazolium cation based ionic liquid onto the pore surface of two types of support, MCM-41 and Vycor. The “grafting to” method was applied, involving (3-chloropropyl)-trialkoxysilane anchoring on the supports’ silanol groups, followed by treatment with 1-methylimidazole and ion exchange with PF6−. Optimum surface pretreatment procedures and reaction conditions for enhanced ionic liquid (IL) loading were properly defined and applied for all modifications. A study on the effect of different pore sizes on the physical state of the grafted 1-(silylpropyl)-3-methylimidazolium-hexafluorophosphate ([spmim][PF6−]) was also conducted. The [spmim][PF6−] crystallinity under extreme confinement in the pores was investigated by modulated differential scanning calorimetry (DSC) and X-ray diffraction (XRD) and was further related to the capacity of the developed SILP to preferentially adsorb CO2 over CO. For this purpose, CO2 and CO absorption measurements of the bulk ionic liquid [bmim][PF6−] and the synthesized alkoxysilyl-IL were initially performed at several temperatures. The results showed an enhancement of the bulk IL performance to preferentially adsorb CO2 at 273 K. The DSC analysis of the SILPs revealed transition of the melting point of the grafted alkoxysilyl-IL to higher temperatures when the support pore size was below 4 nm. The 2.3 nm MCM-41 SILP system exhibited infinite CO2/CO separation capacity at temperatures below and above the melting point of the bulk IL phase, adsorbing in parallel significant amounts of CO2 in a reversible manner. These properties make the developed material an excellent candidate for CO2/CO separation with pressure swing adsorption (PSA) techniques

GnRH-Gemcitabine Conjugates for the Treatment of Androgen-Independent Prostate Cancer: Pharmacokinetic Enhancements Combined with Targeted Drug Delivery

Gemcitabine, a drug with established efficacy against a number of solid tumors, has therapeutic limitations due to its rapid metabolic inactivation. The aim of this study was the development of an innovative strategy to produce a metabolically stable analogue of gemcitabine that could also be selectively delivered to prostate cancer (CaP) cells based on cell surface expression of the Gonadotropin Releasing Hormone-Receptor (GnRH-R). The synthesis and evaluation of conjugated molecules, consisting of gemcitabine linked to a GnRH agonist, is presented along with results in androgen-independent prostate cancer models. NMR and ligand binding assays were employed to verify conservation of microenvironments responsible for binding of novel GnRH-gemcitabine conjugates to the GnRH-R. <i>In vitro</i> cytotoxicity, cellular uptake, and metabolite formation of the conjugates were examined in CaP cell lines. Selected conjugates were efficacious in the <i>in vitro</i> assays with one of them, namely, GSG, displaying high antiproliferative activity in CaP cell lines along with significant metabolic and pharmacokinetic advantages in comparison to gemcitabine. Finally, treatment of GnRH-R positive xenografted mice with GSG showed a significant advantage in tumor growth inhibition when compared to gemcitabine