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1.
RSC Chem Biol ; 2(1): 151-165, 2021 Feb 01.
Article in English | MEDLINE | ID: mdl-34458778

ABSTRACT

Combining different compound classes gives molecular hybrids that can offer access to novel chemical space and unique properties. Peptides provide ideal starting points for such molecular hybrids, which can be easily modified with a variety of molecular entities. The addition of small molecules can improve the potency, stability and cell permeability of therapeutically relevant peptides. Furthermore, they are often applied to create peptide-based tools in chemical biology. In this review, we discuss general methods that allow the discovery of this compound class and highlight key examples of peptide-small molecule hybrids categorised by the application and function of the small molecule entity.

2.
ChemMedChem ; 16(24): 3691-3700, 2021 12 14.
Article in English | MEDLINE | ID: mdl-34259396

ABSTRACT

We report the synthesis and biological evaluation of a light-activated (caged) prodrug of the KDAC inhibitor panobinostat (Zap-Pano). We demonstrate that addition of the 4,5-dimethoxy-2-nitrobenzyl group to the hydroxamic acid oxygen results in an inactive prodrug. In two cancer cell lines we show that photolysis of this compound releases panobinostat and an unexpected carboxamide analogue of panobinostat. Photolysis of Zap-Pano causes an increase in H3K9Ac and H3K18Ac, consistent with KDAC inhibition, in an oesophageal cancer cell line (OE21). Irradiation of OE21 cells in the presence of Zap-Pano results in apoptotic cell death. This compound is a useful research tool, allowing spatial and temporal control over release of panobinostat.


Subject(s)
Antineoplastic Agents/pharmacology , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylases/metabolism , Panobinostat/pharmacology , Prodrugs/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Death/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Histone Deacetylase Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors/chemistry , Humans , Molecular Structure , Panobinostat/chemical synthesis , Panobinostat/chemistry , Prodrugs/chemical synthesis , Prodrugs/chemistry , Structure-Activity Relationship
3.
ChemMedChem ; 16(20): 3185-3188, 2021 10 15.
Article in English | MEDLINE | ID: mdl-34236771

ABSTRACT

The major obstacle in applying peptides to intracellular targets is their low inherent cell permeability. Standard approaches to attach a fluorophore (e. g. FITC, TAMRA) can change the physicochemical properties of the parent peptide and influence their ability to penetrate and localize in cells. We report a label-free strategy for evaluating the cell permeability of cyclic peptide leads. Fluorescent tryptophan analogues 4-cyanotryptophan (4CNW) and ß-(1-azulenyl)-L-alanine (AzAla) were incorporated into in vitro translated macrocyclic peptides by initiator reprogramming. We then demonstrate these efficient blue fluorescent emitters are good tools for monitoring peptide penetration into cells.


Subject(s)
Alanine/analogs & derivatives , Fluorescent Dyes/chemistry , Optical Imaging , Peptides, Cyclic/chemistry , Sesquiterpenes/chemistry , Tryptophan/analogs & derivatives , Alanine/chemistry , Azulenes/chemistry , Cell Line, Tumor , Humans , Molecular Structure , Permeability , Tryptophan/chemistry
4.
Cell Chem Biol ; 28(9): 1258-1270.e13, 2021 09 16.
Article in English | MEDLINE | ID: mdl-33910023

ABSTRACT

Tumor hypoxia is associated with therapy resistance and poor patient prognosis. Hypoxia-activated prodrugs, designed to selectively target hypoxic cells while sparing normal tissue, represent a promising treatment strategy. We report the pre-clinical efficacy of 1-methyl-2-nitroimidazole panobinostat (NI-Pano, CH-03), a novel bioreductive version of the clinically used lysine deacetylase inhibitor, panobinostat. NI-Pano was stable in normoxic (21% O2) conditions and underwent NADPH-CYP-mediated enzymatic bioreduction to release panobinostat in hypoxia (<0.1% O2). Treatment of cells grown in both 2D and 3D with NI-Pano increased acetylation of histone H3 at lysine 9, induced apoptosis, and decreased clonogenic survival. Importantly, NI-Pano exhibited growth delay effects as a single agent in tumor xenografts. Pharmacokinetic analysis confirmed the presence of sub-micromolar concentrations of panobinostat in hypoxic mouse xenografts, but not in circulating plasma or kidneys. Together, our pre-clinical results provide a strong mechanistic rationale for the clinical development of NI-Pano for selective targeting of hypoxic tumors.


Subject(s)
Antineoplastic Agents/pharmacology , Drug Development , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylases/metabolism , Hypoxia/drug therapy , Panobinostat/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Drug Screening Assays, Antitumor , Female , Histone Deacetylase Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors/chemistry , Hypoxia/metabolism , Male , Mice , Mice, Nude , Molecular Structure , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/pathology , Panobinostat/chemical synthesis , Panobinostat/chemistry , Tumor Cells, Cultured
5.
J Org Chem ; 82(21): 11585-11593, 2017 11 03.
Article in English | MEDLINE | ID: mdl-28985675

ABSTRACT

A one-pot catalytic enantioselective allylboration/Mizoroki-Heck reaction of 2-bromoaryl ketones has been developed for the asymmetric synthesis of 3-methyleneindanes bearing a tertiary alcohol center. Brønsted acid-catalyzed allylboration with a chiral BINOL derivative was followed by a palladium-catalyzed Mizoroki-Heck cyclization, resulting in selective formation of the exo-alkene. This novel protocol provides a concise and scalable approach to 1-alkyl-3-methyleneindan-1-ols in high enantiomeric ratios (up to 96:4 er). The potential of these compounds as chiral building blocks was demonstrated with efficient transformation to optically active diol and amino alcohol scaffolds.

6.
Int J Radiat Oncol Biol Phys ; 98(5): 1183-1196, 2017 08 01.
Article in English | MEDLINE | ID: mdl-28721903

ABSTRACT

With the increasing incidence of cancer worldwide, the need for specific, effective therapies is ever more urgent. One example of targeted cancer therapeutics is hypoxia-activated prodrugs (HAPs), also known as bioreductive prodrugs. These prodrugs are inactive in cells with normal oxygen levels but in hypoxic cells (with low oxygen levels) undergo chemical reduction to the active compound. Hypoxia is a common feature of solid tumors and is associated with a more aggressive phenotype and resistance to all modes of therapy. Therefore, the combination of radiation therapy and bioreductive drugs presents an attractive opportunity for synergistic effects, because the HAP targets the radiation-resistant hypoxic cells. Hypoxia-activated prodrugs have typically been precursors of DNA-damaging agents, but a new generation of molecularly targeted HAPs is emerging. By targeting proteins associated with tumorigenesis and survival, these compounds may result in greater selectivity over healthy tissue. We review the clinical progress of HAPs as adjuncts to radiation therapy and conclude that the use of HAPs alongside radiation is vastly underexplored at the clinical level.


Subject(s)
Antineoplastic Agents/metabolism , Molecular Targeted Therapy/methods , Neoplasm Proteins/drug effects , Neoplasms/therapy , Prodrugs/metabolism , Radiation Tolerance/drug effects , Tumor Hypoxia/drug effects , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Clinical Trials as Topic , Combined Modality Therapy/methods , Humans , Neoplasms/metabolism , Phenotype , Prodrugs/chemistry , Prodrugs/pharmacology , Radiation Tolerance/physiology , Tumor Hypoxia/physiology
7.
Chemistry ; 23(5): 1044-1047, 2017 Jan 23.
Article in English | MEDLINE | ID: mdl-27918637

ABSTRACT

A mild, efficient and regioselective method for para-amination of activated arenes has been developed through a combination of iron and copper catalysis. A diverse range of products were obtained from an operationally simple one-pot, two-step procedure involving bromination of the aryl substrate with the powerful Lewis acid iron(III) triflimide, followed by a copper(I)-catalysed N-arylation reaction. This two-step dehydrogenative process for the regioselective coupling of aromatic C-H bonds with non-activated amines was applicable to anisole-, phenol-, aniline- and acetanilide-type aryl compounds. Importantly, the arene substrates were used as the limiting reagent and required no protecting-group manipulations during the transformation.

8.
Cell Microbiol ; 19(3)2017 03.
Article in English | MEDLINE | ID: mdl-27649068

ABSTRACT

HSP90 chaperones are essential regulators of cellular function, as they ensure the appropriate conformation of multiple key client proteins. Four HSP90 isoforms were identified in the protozoan parasite Theileria annulata. Partial characterization was undertaken for three and localization confirmed for cytoplasmic (TA12105), endoplasmic reticulum (TA06470), and apicoplast (TA10720) forms. ATPase activity and binding to the HSP90 inhibitor geldanamycin were demonstrated for recombinant TA12105, and all three native forms could be isolated to varying extents by binding to geldanamycin beads. Because it is essential, HSP90 is considered a potential therapeutic drug target. Resistance to the only specific Theileriacidal drug is increasing, and one challenge for design of drugs that target the parasite is to limit the effect on the host. An in vitro cell culture system that allows comparison between uninfected bovine cells and the T. annulata-infected counterpart was utilized to test the effects of geldanamycin and the derivative 17-AAG. T. annulata-infected cells had greater tolerance to geldanamycin than uninfected cells yet exhibited significantly more sensitivity to 17-AAG. These findings suggest that parasite HSP90 isoform(s) can alter the drug sensitivity of infected host cells and that members of the Theileria HSP90 family are potential targets worthy of further investigation.


Subject(s)
HSP90 Heat-Shock Proteins/analysis , Leukocytes/parasitology , Organelles/enzymology , Protein Isoforms/analysis , Theileria annulata/enzymology , Animals , Cattle , Cells, Cultured
9.
J Org Chem ; 81(20): 9810-9819, 2016 10 21.
Article in English | MEDLINE | ID: mdl-27680202

ABSTRACT

A four-step synthesis of allylic trichloroacetimidates bearing a 2-proparyloxyaryl group has been developed from readily available 2-hydroxybenzaldehydes, and these have been used for the preparation of allylic amide derived 2H-chromenes using an Overman rearrangement and a 6-endo-dig hydroarylation. High yields of the 2H-chromenes were achieved using a stepwise approach involving an Overman rearrangement under thermal conditions followed by a hydroarylation reaction with a gold(I) triflimide catalyst. An alternative method where both reactions were performed as a one-pot process was also developed and instead used a gold(I) chloride catalyst activated by silver(I) hexafluoroantimonate for the cycloisomerization step. The allylic amide derived 2H-chromenes were converted to the corresponding coumarin analogues by a pyridinium dichromate (PDC)-mediated chemoselective allylic oxidation.

10.
J Org Chem ; 81(15): 6697-706, 2016 08 05.
Article in English | MEDLINE | ID: mdl-27414232

ABSTRACT

Rapid access to allylic trichloroacetimidates bearing a 2-allylaminoaryl group from readily available 2-iodoanilines combined with a one-pot multibond forming process has allowed the efficient synthesis of a series of 5-amino-2,5-dihydro-1H-benzo[b]azepines. The potential of these compounds as synthetic building blocks was demonstrated by the preparation of a late-stage intermediate of the hyponatremia agent, mozavaptan.

11.
Org Lett ; 17(10): 2514-7, 2015 May 15.
Article in English | MEDLINE | ID: mdl-25933177

ABSTRACT

A novel, one-pot allylboration-Heck reaction of 2-bromobenzaldehydes has been developed for the general and efficient synthesis of 3-methyleneindan-1-ols. Modification of the one-pot procedure to include chiral Brønsted acid catalyzed allylation has allowed the preparation of these building blocks in high enantioselectivity and excellent yields.

12.
J Org Chem ; 80(9): 4683-96, 2015 May 01.
Article in English | MEDLINE | ID: mdl-25847814

ABSTRACT

A one-pot multibond-forming process involving a thermally mediated Overman rearrangement and a ring closing metathesis reaction of allylic trichloroacetimidates bearing a 2-allyloxyaryl group has been developed for the synthesis of 5-amino-substituted 2,5-dihydro-1-benzoxepines. Chemoselective reduction and functionalization of these compounds allowed access to a range of pharmacologically active 5-amino-2,3,4,5-tetrahydro-1-benzoxepine scaffolds.


Subject(s)
Benzoxepins/chemical synthesis , Heterocyclic Compounds/chemical synthesis , Benzoxepins/chemistry , Cyclization , Heterocyclic Compounds/chemistry , Molecular Structure
13.
J Org Chem ; 79(16): 7633-48, 2014 Aug 15.
Article in English | MEDLINE | ID: mdl-25060853

ABSTRACT

Allylic trichloroacetimidates bearing a 2-vinyl or 2-allylaryl group have been designed as substrates for a one-pot, two-step multi-bond-forming process leading to the general preparation of aminoindenes and amino-substituted 1,4-dihydronaphthalenes. The synthetic utility of the privileged structures formed from this one-pot process was demonstrated with the total synthesis of four oxybenzo[c]phenanthridine alkaloids, oxychelerythrine, oxysanguinarine, oxynitidine, and oxyavicine. An intramolecular biaryl Heck coupling reaction, catalyzed using the Hermann-Beller palladacycle was used to effect the key step during the synthesis of the natural products.


Subject(s)
Alkaloids/chemical synthesis , Biological Products/chemistry , Biological Products/chemical synthesis , Indenes/chemistry , Indenes/chemical synthesis , Naphthalenes/chemistry , Phenanthridines/chemistry , Phenanthridines/chemical synthesis , Acetamides/chemistry , Alkaloids/chemistry , Cyclization , Molecular Structure , Stereoisomerism , Vinyl Compounds/chemistry
14.
Chemistry ; 20(31): 9762-9, 2014 Jul 28.
Article in English | MEDLINE | ID: mdl-24989672

ABSTRACT

A stereodivergent asymmetric Lewis base catalyzed Michael addition/lactonization of enone acids into substituted dihydrobenzofuran and tetrahydrofuran derivatives is reported. Commercially available (S)-(-)-tetramisole hydrochloride gives products with high syn diastereoselectivity in excellent enantioselectivity (up to 99:1 d.r.syn/anti , 99 % eesyn ), whereas using a cinchona alkaloid derived catalyst gives the corresponding anti-diastereoisomers as the major product (up to 10:90 d.r.syn/anti , 99 % eeanti ).


Subject(s)
Benzofurans/chemical synthesis , Furans/chemical synthesis , Benzofurans/chemistry , Catalysis , Furans/chemistry , Stereoisomerism
15.
J Org Chem ; 78(14): 7223-33, 2013 Jul 19.
Article in English | MEDLINE | ID: mdl-23795558

ABSTRACT

Two variations of the Overman rearrangement have been developed for the highly selective synthesis of anti-vicinal amino alcohol natural products. A MOM ether-directed palladium(II)-catalyzed rearrangement of an allylic trichloroacetimidate was used as the key step for the preparation of the protein kinase C inhibitor D-erythro-sphinganine and the antitumor agent (+)-spisulosine, whereas the Overman rearrangement of chiral allylic trichloroacetimidates generated by the asymmetric reduction of an α,ß-unsaturated methyl ketone allowed rapid access both to D-ribo-phytosphingosine and L-arabino-phytosphingosine.


Subject(s)
Lipids/chemical synthesis , Sphingosine/analogs & derivatives , Sphingosine/chemical synthesis , Lipids/chemistry , Molecular Conformation , Sphingosine/chemistry
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