Design, Synthesis, and Biological Evaluation of 1-(Indolizin-3-yl)ethan-1-ones as CBP Bromodomain Inhibitors for the Treatment of Prostate Cancer.

CREB (cyclic-AMP responsive element binding protein) binding protein (CBP) is a potential target for prostate cancer treatment. Herein, we report the structural optimization of a series of 1-(indolizin-3-yl)ethan-1-one compounds as new selective CBP bromodomain inhibitors, aiming to improve cellular potency and metabolic stability. This process led to compound 9g (Y08284), which possesses good liver microsomal stability and pharmacokinetic properties (F = 25.9%). Furthermore, the compound is able to inhibit CBP bromodomain as well as the proliferation, colony formation, and migration of prostate cancer cells. Additionally, the new inhibitor shows promising antitumor efficacy in a 22Rv1 xenograft model (TGI = 88%). This study provides new lead compounds for further development of drugs for the treatment of prostate cancer.

C-H/C-C Functionalization Approach to N-Fused Heterocycles from Saturated Azacycles.

Herein we report the synthesis of substituted indolizidines and related N-fused bicycles from simple saturated cyclic amines through sequential C-H and C-C bond functionalizations. Inspired by the Norrish-Yang Type II reaction, C-H functionalization of azacycles is achieved by forming α-hydroxy-ß-lactams from precursor α-ketoamide derivatives under mild, visible light conditions. Selective cleavage of the distal C(sp2)-C(sp3) bond in α-hydroxy-ß-lactams using a Rh-complex leads to α-acyl intermediates which undergo sequential Rh-catalyzed decarbonylation, 1,4-addition to an electrophile, and aldol cyclization, to afford N-fused bicycles including indolizidines. Computational studies provide mechanistic insight into the observed positional selectivity of C-C cleavage, which depends strongly on the groups bound to Rh trans to the phosphine ligand.

Enantioselective synthesis of an octahydroindolizine (indolizidine) alcohol using an enzymatic resolution.

A homo-chiral synthesis of (7R,8aS)-octahydro-5,5-dimethylindolizin-7-amine 8 and (7S, 8aS)-octahydro-5,5-dimethylindolizin-7-ol 9, amine building blocks which have found applications within the pharmaceutical industry, is presented. The approach uses a Novozym 435-mediated kinetic resolution of racemic octahydroindolizine (indolizidine) alcohol 13 as a key step (up to 100 g scale).

A Short and Efficient Synthesis of Iminosugar 2-Acyl Indolizidine.

A facile and convergent approach has been developed for the stereoselective construction of biologically important polyhydroxylated 2-acyl indolizidine framework using aza-Cope rearrangement-Mannich cyclization as a key step. The generality of this methodology is demonstrated with various lactol-tosylates derived from carbohydrates. The presented method provides an easy access to indolizidine- and tetrahydroindolizine-based iminosugar derivatives in good yields.

CAT3, a novel agent for medulloblastoma and glioblastoma treatment, inhibits tumor growth by disrupting the Hedgehog signaling pathway.

Medulloblastoma (MB) and glioblastoma (GBM) are the most prevalent malignant brain tumors. The identification of novel therapeutic strategies is urgent for MB and GBM patients. Herein, we discovered 13a-(S)-3-Hydroxyl-6,7-dimethoxyphenanthro[9,10-b]-indolizidine (PF403) strongly exhibited inhibitory activity against Hedgehog (Hh) pathway-hyperactivated MB and GBM cells with a 50% inhibitory concentration (IC50) of 0.01 nM. CAT3 was designed and synthesized as the prodrug of PF403 and displayed significant in vivo efficacy against MB and GBM. Mechanistic study revealed that CAT3 inhibited MB and GBM primarily by interrupting the Hh signaling pathway. At the molecular level, PF403 inhibited the cell surface accumulation of the Smoothened (Smo) receptor by directly binding or enhancing the interaction of Smo with the repressor Ptch1. Furthermore, PF403 significantly repressed Gli1 nuclear accumulation and transcription by promoting Sufu-Gli1 and PKA-Gli1 interactions. Collectively, our studies support the hypothesis that CAT3 is a promising therapeutic agent for the treatment of Hh-driven MB and GBM.

A short and modular approach towards 3,5-disubstituted indolizidine alkaloids.

3,5-Dialkyl indolizidines have been prepared in four linear steps from commercially available starting materials. The sequence involves two direct α-functionalization steps and a subsequent reductive amination and provides diastereoselective access to both C-3 epimers of the 5,9-trans-substituted indolizines. The naturally occurring indolizidines 195B and 223AB have been synthesized using this methodology.

Highly Chemoselective Synthesis of Indolizidine Lactams by SmI2 -Induced Umpolung of the Amide Bond via Aminoketyl Radicals: Efficient Entry to Alkaloid Scaffolds.

Samarium(II) iodide enables a wide range of highly chemoselective umpolung radical transformations proceeding by electron transfer to carbonyl groups; however, cyclizations of important nitrogen-containing precursors have proven limited due to their prohibitive redox potential. Herein, we report the first reductive cyclizations of unactivated cyclic imides onto N-tethered olefins using SmI2 /H2 O. This new umpolung protocol leads to the rapid synthesis of nitrogen-containing heterocycles that are of particular significance as precursors to pharmaceutical pharmacophores and numerous classes of alkaloids. The reaction conditions tolerate a wide range of functional groups. Excellent chemoselectivity is observed in the cyclization over amide and ester functional groups. Such unconventional reactivity has important implications for the design and optimization of new bond-forming reactions by umpolung radical processes. The reaction advances the SmI2 cyclization platform to the challenging unactivated N-tethered acyl-type radical precursors to access nitrogen-containing architectures.

Molecular Modeling, Synthesis, and Anti-HIV Activity of Novel Isoindolinedione Analogues as Potent Non-nucleoside Reverse Transcriptase Inhibitors.

Different isoindolinedione derivatives bearing imine, amide, thioamide, and sulfonamide linkages have been designed in silico using discovery studio software (BIOVIA, San Diego, CA, USA), synthesized, and evaluated for their anti-HIV activity. SAR studies revealed that the linkages in these molecules did affect their anti-HIV activity and the molecules having sulfonamide linkages were the most potent HIV-RT inhibitors as the S=O bonds of the sulfonamide moiety interacted with Lys103 (NH or carbonyl or both) and Pro236; the NH part of the sulfonamide linkage formed bond with carbonyl of Lys101. blood-brain barrier (BBB) plots were also studied, and it was found that all the designed molecules have potential to cross BBB, a very vital criteria for anti-HIV drugs. In vitro screening was performed using HIV-1 strain IIIB in MT-4 cells using the MTT assay, and it was seen that some of these molecules were effective inhibitors of HIV-1 replication at nanomolar concentration with selectivity indices ranging from 33.75 to 73.33 under in vitro conditions. Some of these molecules have shown good anti-HIV activity at 3-4 nm concentrations. These derivatives have potential to be developed as lead molecules effective against HIV-1. Novel isoindolinedione derivatives as probable NNRTIs have been synthesized and characterized. Some of these molecules have shown good anti-HIV activity at 3-4 nm concentrations.

Synthesis of Azabicycles via Cascade Aza-Prins Reactions: Accessing the Indolizidine and Quinolizidine Cores.

The first detailed studies of intramolecular aza-Prins and aza-silyl-Prins reactions, starting from acyclic materials, are reported. The methods allow rapid and flexible access toward an array of [6,5] and [6,6] aza-bicycles, which form the core skeletons of various alkaloids. On the basis of our findings on the aza-Prins and aza-silyl-Prins cyclizations, herein we present simple protocols for the intramolecular preparation of the azabicyclic cores of the indolizidines and quinolizidines using a one-pot cascade process of N-acyliminium ion formation followed by aza-Prins cyclization and either elimination or carbocation trapping. It is possible to introduce a range of different substituents into the heterocycles through a judicial choice of Lewis acid and solvent(s), with halo-, phenyl-, and amido-substituted azabicyclic products all being accessed through these highly diastereoselective processes.

Quaternary Indolizidine and Indolizidone Iminosugars as Potential Immunostimulating and Glycosidase Inhibitory Agents: Synthesis, Conformational Analysis, Biological Activity, and Molecular Docking Study.

New quaternary indolizidine iminosugars, with hydroxymethyl group at the ring junction, namely, C-8a-hydroxymethyl-1-deoxycastanospermine congeners 1a, 2a, 3a and their 3-oxo analogs 1b, 2b, and 3b were synthesized by using intramolecular reductive aminocyclization/lactamization of d-mannose/D-glucose derived C5-γ-azido esters as a key step wherein both the rings of the indolizidine skeleton were built up in one pot following the cascade reaction pathway. The conformations ((5)C8 or (8)C5) of 1-3 were assigned on the basis of the (1)H NMR studies. All compounds were found to be potent inhibitors of various glycosidase enzymes with Ki and IC50 values in the micromolar/nanomolar concentration range and further substantiated by molecular docking studies. The effect of synthesized iminosugars 1-3 on the cytokine secretion of IL-4, IL-6, and IFN-γ was evaluated. All compounds were found to be TH1 bias increasing the TH1/TH2 cytokines ratio (IL-6 and IL-4) indicating their potency as immunostimulating agents. Our study suggests that immunomodulatory activity of indolizidine iminosugars can be tuned by minor structural/stereochemical alterations.

Hydroxymethyl-Branched Polyhydroxylated Indolizidines: Novel Selective α-Glucosidase Inhibitors.

α,α-Disubstituted piperidines and conformationally constrained polyhydroxylated indolizidines bearing a hydroxymethyl substituent in position 8a were synthesized from a readily available l-sorbose-derived ketonitrone. Diastereoselective vinylation under two sets of complementary conditions allowed access to both configurations of the newly formed quaternary stereocenter. Subsequent N-allylation and ring-closing metathesis afforded 8a-branched indolizidines in high yield. The newly prepared iminosugars demonstrated highly potent inhibition of α-glucosidases. Most interestingly, compound 9b exhibits very high selectivity toward this class of enzymes, with an unusual mode of binding.

Direct synthesis of imino-C-nucleoside analogues and other biologically active iminosugars.

Iminosugars have attracted increasing attention as chemical probes, chaperones and leads for drug discovery. Despite several clinical successes, their de novo synthesis remains a significant challenge that also limits their integration with modern high-throughput screening technologies. Herein, we describe a unique synthetic strategy that converts a wide range of acetaldehyde derivatives into iminosugars and imino-C-nucleoside analogues in two or three straightforward transformations. We also show that this strategy can be readily applied to the rapid production of indolizidine and pyrrolizidine iminosugars. The high levels of enantio- and diastereoselectivity, excellent overall yields, convenience and broad substrate scope make this an appealing process for diversity-oriented synthesis, and should enable drug discovery efforts.

Redox cycloisomerization approach to 1,2-dihydropyridines.

The phosphine-catalyzed synthesis of 1,2-dihydropyridines via an alkyne isomerization/electrocyclization sequence is described. Propargylidenecarbamate substrates were prepared following a one-pot procedure between a terminal alkyne, a benzonitrile, and a chloroformate in the presence of trimethylaluminum. This methodology gives access to a diverse set of 2,6-disubstituted 1,2-dihydropyridines in high yield. The products can be easily converted into substituted piperidines or pyridines, and this methodology was applied to the synthesis of indolizidines.

Selective hydrogenation of indolizines: an expeditious approach to derive tetrahydroindolizines and indolizidines from morita-baylis-hillman adducts.

In this study, we describe the hydrogenation of indolizines derived from Morita-Baylis-Hillman adducts. We demonstrate that functionalized tetrahydroindolizines and indolizidines can be prepared selectively, at low pressure, by simply adjusting the acidity of the medium. Using this simple and straightforward strategy, substituted tetrahydroindolizines and indolizidines were obtained diastereoselectively in high yield.

Merging asymmetric Henry reaction with organocatalytic cascade reaction for the construction of a chiral indolizidine alkaloid skeleton.

A sequential reaction combining the copper-catalyzed asymmetric Henry reaction with the organocatalytic Michael addition-hemiacetalization cascade reaction was developed. The C1-symmetric chiral diamine L1-copper complex was responsible for the first highly enantioselective Henry reaction, while diphenylprolinol silyl ether A acted as effective organocatalyst for the second cascade reaction between chiral ß-nitro alcohol and α,ß-unsaturated aldehydes. Via rational design and combination of the two independent catalytic systems, good yields and excellent enantioselectivities and diastereoselectivities were achieved for a broad substrate scope under mild reaction conditions. The synthetic utility of this sequential catalytic asymmetric cascade reaction was demonstrated as an alternative and straightforward stereoselective synthesis strategy for chiral indolizidine alkaloid and its analogues.

Enantioselective synthesis of benzoindolizidine derivatives using chiral phase-transfer catalytic intramolecular domino aza-Michael addition/alkylation.

An efficient and enantioselective strategy to synthesize benzoindolizidines from α,ß-unsaturated amino ketones via domino intramolecular aza-Michael addition/alkylation was developed. These reactions were enabled by cinchona alkaloid-derived quaternary ammonium salts as the phase-transfer catalyst. A variety of benzoindolizidines were prepared in good yields (up to 93%) and enantioselectivities (up to 92.8:7.2 er).

Stereoselective nucleophilic addition of PhSCF2 SiMe3 to chiral cyclic nitrones: asymmetric synthesis of gem-difluoromethylenated polyhydroxypyrrolizidines and -indolizidines.

Fluoride-catalyzed nucleophilic addition of a difluoro(phenylsulfanyl)methyl group ("PhSCF2 ") generated from PhSCF2 SiMe3 to nitrones was accomplished in satisfactory yields. High diastereoselectivities were observed with chiral polyoxygenated cyclic nitrones to provide the corresponding adducts, which were further manipulated to afford gem-difluoromethylenated polyhydroxypyrrolizidines and -indolizidines.

Divergent total synthesis of the tricyclic marine alkaloids lepadiformine, fasicularin, and isomers of polycitorols by reagent-controlled diastereoselective reductive amination.

We describe a flexible and divergent route to the pyrrolo-/pyrido[1,2-j]quinoline frameworks of tricyclic marine alkaloids via a common intermediate formed by the ester-enolate Claisen rearrangement of a cyclic amino acid allylic ester. We have synthesized the proposed structure of polycitorols and demonstrated that the structure of these alkaloids requires revision. In addition to asymmetric formal syntheses, stereoselective and concise total syntheses of (-)-lepadiformine and (-)-fasicularin were also accomplished from simple, commercially available starting materials in a completely substrate-controlled manner. The key step in these total syntheses was the reagent-dependent stereoselective reductive amination of the common intermediate to yield either indolizidines 55 a or 55 b. Aziridinium-mediated carbon homologation of the hindered C-10 group to the homoallylic group facilitated the synthesis.

Synthesis of isofagomine-pyrrolidine hybrid sugars and analogues of (-)-steviamine and (+)-hyacinthacine C5 using 1,3-dipolar cycloaddition reactions.

Highly regioselective 1,3-dipolar cycloadditions between d-arabinose-derived nitrones and d-mannitol-derived trans-olefins have been utilized to synthesize isofagomine-pyrrolidine hybrid sugars, hydroxymethylated analogues of (-)-steviamine and analogues of (+)-hyacinthacine C5. All of the new compounds were subsequently tested against several commercially available glycosidases, and some of them showed good and selective glycosidase inhibition.

Synthesis of polyhydroxylated quinolizidine and indolizidine scaffolds from sugar-derived lactams via a one-pot reduction/Mannich/Michael sequence.

A direct approach to the synthesis of indolizidine and quinolizidine scaffolds of iminosugars is described. The presented strategy is based on a one-pot sugar lactam reduction with Schwartz's reagent followed by a diastereoselective Mannich/Michael tandem reaction of the resulting sugar imine with Danishefsky's diene. The stereochemical course of the investigated reaction has been explained in detail. The obtained bicyclic products are attractive building blocks for the synthesis of various naturally occurring polyhydroxylated alkaloids and their derivatives.