Rational Design and Asymmetric Synthesis of Potent and Neurotrophic Ligands for FK506‐Binding Proteins (FKBPs)

To create highly efficient inhibitors for FK506‐binding proteins, a new asymmetric synthesis for pro‐(S)‐C⁵‐branched [4.3.1] aza‐amide bicycles was developed. The key step of the synthesis is an HF‐driven N‐acyliminium cyclization. Functionalization of the C⁵ moiety resulted in novel protein contacts with the psychiatric risk factor FKBP51, which led to a more than 280‐fold enhancement in affinity. The most potent ligands facilitated the differentiation of N2a neuroblastoma cells with low nanomolar potency.     

Tetrasubstituted Phenanthrolines as Highly Potent,Water‐Soluble,and Selective G‐Quadruplex Ligands

Small molecules capable of stabilizing the G‐quadruplex (G4) structure are of interest for the development of improved anticancer drugs. Novel 4,7‐diamino‐substituted 1,10‐phenanthroline‐2,9‐dicarboxamides that represent hybrid structures of known phenanthroline‐based ligands have been designed. An efficient synthetic route to the compounds has been developed and their interactions with various G4 sequences have been evaluated by Förster resonance energy transfer (FRET) melting assays, fluorescent intercalator displacement (FID), electrospray ionization mass spectrometry (ESI‐MS), and circular dichroism (CD) spectroscopy. The preferred compounds have high aqueous solubility and are strong and potent G4 binders with a high selectivity over duplex DNA; thus, they represent a significant improvement over the lead compounds. Two of the compounds are inhibitors of HeLa and HT1080 cell proliferation.     

One‐Step Synthetic Access to Isosteric and Potent Anticancer Nitrogen Heterocycles with the Benzo[c]phenanthridine Scaffold

A versatile one‐step two‐component cyclization to build new tetracyclic nitrogen heterocycles is described. Ortho‐methylhetarenecarbonitrile components were condensed with aldehydes to access a large library of differently substituted ring systems. The heterocyclic core can be easily modified by variation of the position of the endocyclic nitrogen atom in the o‐methylhetarenecarbonitrile substrate. The manner of the nucleophilic attack that leads to the condensation can be triggered by different electron‐density distribution in the molecule induced by the position of the nitrogen atom. Taking this into account, there is an electronic preference that leads to either pyridophenanthrolines or the corresponding pyridoazacarbazoles as the main products. We demonstrate the high antitumor potential of some of our synthesized heterocycles, which is strongly dependent on the substitution pattern introduced through the aldehyde component. The position and number of endocyclic nitrogen atoms play an important role regarding cytotoxicity of the studied compounds.     

Organocatalytic Enantioselective Synthesis of Chiral Allenes: Remote Asymmetric 1,8‐Addition of Indole Imine Methides

An organocatalytic enantioconvergent synthesis of chiral tetrasubstituted allenes is disclosed. With suitable chiral phosphoric acid catalysts, a range of racemic indole‐substituted propargylic alcohols reacted with nucleophiles to provide efficient access to a series of enantioenriched allenes with high enantioselectivities. Control experiments suggested a mechanism involving remotely controlled asymmetric 1,8‐addition of the in situ generated indole imine methide via a bifunctional transition state.     

Enantio‐ and Diastereoselective Access to Distant Stereocenters Embedded within Tetrahydroxanthenes: Utilizing ortho‐Quinone Methides as Reactive Intermediates in Asymmetric Brønsted Acid Catalysis

A protocol for the highly enantioselective synthesis of 9‐substituted tetrahydroxanthenones by means of asymmetric Brønsted acid catalysis has been developed. A chiral binol‐based N‐triflyphosphoramide was found to promote the in situ generation of ortho‐quinone methides and their subsequent reaction with 1,3‐cyclohexanedione to provide the desired products with excellent enantioselectivities. In addition, a highly enantio‐ and diastereoselective Brønsted acid catalyzed desymmetrization of 5‐monosubstituted 1,3‐dicarbonyl substrates with ortho‐quinone methides gives rise to valuable tetrahydroxanthenes containing two distant stereocenters.     

Efficient Synthesis of Cryptophycin‐52 and Novel para‐Alkoxymethyl Unit A Analogues

Cryptophycins are a family of highly cytotoxic, cyclic depsipeptides. They display antitumour activity that is largely maintained for multi‐drug‐resistant tumour cells. Cryptophycins are composed of four building blocks (units A–D) that correspond to the respective amino and hydroxy acids. A new synthetic route to unit A allows the selective generation of all four stereogenic centres in a short, efficient and reliable synthesis and contributes to an easier and faster synthesis of cryptophycins. The first two stereogenic centres are introduced by a catalytic asymmetric dihydroxylation, whereas the remaining two stereogenic centres are introduced with substrate control of diastereoselectivity. The stereogenic diol function also serves as the epoxide precursor. The approach was used to synthesise the native unit A building block as well as three para‐alkoxymethyl analogues from which cryptophycin‐52 and three analogous cryptophycins were prepared. Macrocyclisation of the seco‐depsipeptides was based on ring‐closing metathesis.     

Access to trans‐3,4‐Dihydroxy‐2‐alkylpyrrolidines and Piperidines by Use of Stereodefined Cyclic N,O‐Acetals as a Diversity‐Generating Element

A highly efficient and stereoselective synthetic pathway towards trans‐3,4‐dihydroxy‐2‐alkylpyrrolidines and piperidines is described. The nature of the protecting groups on the hydroxyl moieties played a crucial role on the trans selectivity. By using this method, a concise total synthesis of (?)‐2‐epilentiginosine has been achieved.     

Asymmetric α‐Hydroxylation of Tetralone‐Derived β‐Ketoesters by Using a Guanidine–Urea Bifunctional Organocatalyst in the Presence of Cumene Hydroperoxide

Highly enantioselective catalytic oxidation of 1‐tetralone‐derived β‐keto esters was achieved by using a guanidine–urea bifunctional organocatalyst in the presence of cumene hydroperoxide (CHP), a safe, commercially available oxidant. The α‐hydroxylation products were obtained in 99 % yield with up to 95 % enantiomeric excess (ee). The present oxidation was successfully applied to synthesize a key intermediate of the anti‐cancer agent daunorubicin ( 2 ).     

Ruthenium–Arene–β‐Carboline Complexes as Potent Inhibitors of Cyclin‐Dependent Kinase 1: Synthesis,Characterization and Anticancer Mechanism Studies

A series of Ru^II–arene complexes ( 1 – 6 ) of the general formula [(η⁶‐arene)Ru(L)Cl]PF₆ (arene=benzene or p‐cymene; L=bidentate β‐carboline derivative, an indole alkaloid with potential cyclin‐dependent kinases (CDKs) inhibitory activities) is reported. All the complexes were fully characterized by classical analytical methods, and three were characterized by X‐ray crystallography. Hydrolytic studies show that β‐carboline ligands play a vital role in their aqueous behaviour. These complexes are highly active in vitro, with the most active complex 6 displaying a 3‐ to 12‐fold higher anticancer activity than cisplatin against several cancer cell lines. Interestingly, the complexes are able to overcome cross‐resistance to cisplatin, and show much lower cytotoxicity against normal cells. Complexes 1 – 6 may directly target CDK1, because they can block cells in the G2M phase, down‐regulate the expression of CDK1 and cyclin B1, and inhibit CDK1/cyclin B in vitro. Further mechanism studies show that the complexes can effectively induce apoptosis through mitochondrial‐related pathways and intracellular reactive oxygen species (ROS) elevation.     

Synthesis and Biological Evaluation of Several Dephosphonated Analogues of CMP‐Neu5Ac as Inhibitors of GM3‐Synthase

Previous studies demonstrated that reducing the GM3 content in myoblasts increased the cell resistance to hypoxic stress, suggesting that a pharmacological inhibition of the GM3 synthesis could be instrumental for the development of new treatments for ischemic diseases. Herein, the synthesis of several dephosphonated CMP‐Neu5Ac congeners and their anti ‐ GM3‐synthase activity is reported. Biological activity testes revealed that some inhibitors almost completely blocked the GM3‐synthase activity in vitro and reduced the GM3 content in living embryonic kidney 293A cells, eventually activating the epidermal growth factor receptor (EGFR) signaling cascade.     

Synthesis and Biological Activities of Simplified Analogs of the Natural PKC Ligands,Bryostatin‐1 and Aplysiatoxin

Protein kinase C (PKC) isozymes play central roles in signal transduction on the cell surface and could serve as promising therapeutic targets of intractable diseases like cancer, Alzheimer's disease, and acquired immunodeficiency syndrome (AIDS). Although natural PKC ligands like phorbol esters, ingenol esters, and teleocidins have the potential to become therapeutic leads, most of them are potent tumor promoters in mouse skin. By contrast, bryostatin‐1 (bryo‐1) isolated from marine bryozoan is a potent PKC activator with little tumor‐promoting activity. Numerous investigations have suggested bryo‐1 to be a promising therapeutic candidate for the above intractable diseases. However, there is a supply problem of bryo‐1 both from natural sources and by organic synthesis. Recent approaches on the synthesis of bryo‐1 have focused on its simplification, without decreasing the ability to activate PKC isozymes, to develop new medicinal leads. Another approach is to use the skeleton of natural PKC ligands to develop bryo‐1 surrogates. We have recently identified 10‐methyl‐aplog‐1 ( 26 ), a simplified analog of tumor‐promoting aplysiatoxin (ATX), as a possible therapeutic lead for cancer. This review summarizes recent investigations on the simplification of natural PKC ligands, bryo‐1 and ATX, to develop potential medicinal leads.     

Morita–Baylis–Hillman Reaction of β,β‐Disubstituted Enones: An Enantioselective Organocatalytic Approach for the Synthesis of Cyclopenta[b]annulated Arenes and Heteroarenes

The first enantioselective organocatalytic intramolecular Morita–Baylis–Hillman (MBH) reaction of sterically highly demanding β,β‐disubstituted enones is presented. The MBH reaction of β,β‐disubstituted‐α,β‐unsaturated electron‐withdrawing systems was previously considered to be unfeasible. Towards this end, designer substrates, which under simple and practical reaction conditions generate a variety of cyclopenta[b]annulated arenes and heteroarenes in excellent enantiopurities and near‐quantitative yields in remarkably short reaction times, are described. The reason for the unusually facile nature of this reaction is attributed to the synergy guided and entropically favored intramolecular reaction. Further, this strategy provides easy access to a substantial number of bioactive natural products and pharmaceutically significant compounds.     

Highly Enantioselective Synthesis of β‐Aminophosphinates with Two Stereogenic Atoms and Their Conversion into Optically Pure Ethyl β‐Amino‐H‐phosphinates

β‐Amino acid analogues : The nucleophilic addition of ethyl (diethoxyethyl)methylphosphinate to a variety of (S)‐(tert‐butanesulfinyl)imines leads to the isolation of two enantioenriched β‐aminophosphinates (>95 % ee; see scheme). Subsequent removal of the protecting groups through pivotal metal‐catalyzed thiophenolysis leads to optically pure ethyl β‐amino‐H‐phosphinates.