Intraoperative Guidance of Pancreatic Cancer Resection Using a Toll-like Receptor 2-Targeted Fluorescence Molecular Imaging Agent.

Unlabelled: To increase the achievement of negative R0 surgical margins and increase the low survival rates of pancreatic cancer, improvements in assessing tumor margins during surgical resections are needed. This can be accomplished by using pancreatic cancer-targeted fluorescence molecular imaging agents to intraoperatively detect tumor margins in real time. Because Toll-like receptor 2 (TLR2) is broadly expressed among many cancer types including pancreatic adenocarcinomas, a high-affinity TLR2-targeted fluorescence molecular imaging agent (TLR2L-800) was developed.

Bioactivity improvement via display of the hydrophobic core of HYD1 in a cyclic β-hairpin-like scaffold, MTI-101.

HYD1 is an all D-amino acid linear 10-mer peptide that was discovered by one-bead-one-compound screening. HYD1 has five hydrophobic amino acids flanked by polar amino acids. Alanine scanning studies showed that alternating hydrophobic amino acid residues and N- and C-terminal lysine side chains were contributors to the biological activity of the linear 10-mer analogs.

Lipophilicity Determines Routes of Uptake and Clearance, and Toxicity of an Alpha-Particle-Emitting Peptide Receptor Radiotherapy.

Lipophilicity is explored in the biodistribution (BD), pharmacokinetics (PK), radiation dosimetry (RD), and toxicity of an internally administered targeted alpha-particle therapy (TAT) under development for the treatment of metastatic melanoma. The TAT conjugate is comprised of the chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate), conjugated to melanocortin receptor 1 specific peptidic ligand (MC1RL) using a linker moiety and chelation of the Ac radiometal. A set of conjugates were prepared with a range of lipophilicities (log values) by varying the chemical properties of the linker.

Biodistribution and Multicompartment Pharmacokinetic Analysis of a Targeted α Particle Therapy.

Targeted α particle therapy (TAT) is ideal for treating disease while minimizing damage to surrounding nontargeted tissues due to short path length and high linear energy transfer (LET). We developed a TAT for metastatic uveal melanoma, targeting the melanocortin-1 receptor (MC1R), which is expressed in 94% of uveal melanomas. Two versions of the therapy are being investigated: Ac-DOTA-Ahx-MC1RL (Ac-Ahx) and Ac-DOTA-di-d-Glu-MC1RL (Ac-di-d-Glu).

Development of Targeted Alpha Particle Therapy for Solid Tumors.

Targeted alpha-particle therapy (TAT) aims to selectively deliver radionuclides emitting α-particles (cytotoxic payload) to tumors by chelation to monoclonal antibodies, peptides or small molecules that recognize tumor-associated antigens or cell-surface receptors. Because of the high linear energy transfer (LET) and short range of alpha (α) particles in tissue, cancer cells can be significantly damaged while causing minimal toxicity to surrounding healthy cells. Recent clinical studies have demonstrated the remarkable efficacy of TAT in the treatment of metastatic, castration-resistant prostate cancer.

Melanocortin 1 Receptor-Targeted α-Particle Therapy for Metastatic Uveal Melanoma.

New effective therapies are greatly needed for metastatic uveal melanoma, which has a very poor prognosis with a median survival of less than 1 y. The melanocortin 1 receptor (MC1R) is expressed in 94% of uveal melanoma metastases, and a MC1R-specific ligand (MC1RL) with high affinity and selectivity for MC1R was previously developed. The Ac-DOTA-MC1RL conjugate was synthesized in high radiochemical yield and purity and was tested in vitro for biostability and for MC1R-specific cytotoxicity in uveal melanoma cells, and the lanthanum-DOTA-MC1RL analog was tested for binding affinity.

Structure and properties of DOTA-chelated radiopharmaceuticals within the Ac decay pathway.

The successful delivery of toxic cargo directly to tumor cells is of primary importance in targeted (α) particle therapy. Complexes of radioactive atoms with the 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelating agent are considered as effective materials for such delivery processes. The DOTA chelator displays high affinity to radioactive metal isotopes and retains this capability after conjugation to tumor targeting moieties.

MTI-101 (cyclized HYD1) binds a CD44 containing complex and induces necrotic cell death in multiple myeloma.

Our laboratory recently reported that treatment with the d-amino acid containing peptide HYD1 induces necrotic cell death in multiple myeloma cell lines. Because of the intriguing biological activity and promising in vivo activity of HYD1, we pursued strategies for increasing the therapeutic efficacy of the linear peptide. These efforts led to a cyclized peptidomimetic, MTI-101, with increased in vitro activity and robust in vivo activity as a single agent using two myeloma models that consider the bone marrow microenvironment.

Tetra-methyl anthracene-2,3,6,7-tetra-carboxyl-ate-tetra-methyl 9,10-dihydro-9,10-dioxoanthracene-2,3,6,7-tetra-carboxyl-ate (1/1).

In the title co-crystal, C(22)H(16)O(10)·C(22)H(18)O(8), the independent tetra-methyl 9,10-dihydro-9,10-dioxoanthracene-2,3,6,7-tetra-carboxyl-ate, (I), and tetra-methyl anthracene-2,3,6,7-tetra-carboxyl-ate, (II), components occupy separate crystallographic inversion centers. In (II), the dihedral angles between the mean aromatic plane and the two independent carboxyl-ate planes are 41.32 (10) and -38.

Acquisition of resistance toward HYD1 correlates with a reduction in cleaved α4 integrin expression and a compromised CAM-DR phenotype.

We recently reported that the β1 integrin antagonist, referred to as HYD1, induces necrotic cell death in myeloma cell lines as a single agent using in vitro and in vivo models. In this article, we sought to delineate the determinants of sensitivity and resistance toward HYD1-induced cell death. To this end, we developed an HYD1 isogenic resistant myeloma cell line by chronically exposing H929 myeloma cells to increasing concentrations of HYD1.

1,2-Dihydro-9H-carbazole-4(3H)-thione.

The crystal structure of the title compound, C(12)H(11)NS, features parallel chains of alternating N-H⋯S hydrogen-bonded mirror-image conformers along [10[Formula: see text]]. The mol-ecular conformation is that of an envelope, with all of the framework atoms except one close to a mean plane (rms deviation 0.054 Å); one C atom of the cyclo-hexene-thione ring forms the envelope flap, which makes a dihedral angle of 48.

Facile iterative synthesis of 2,5-terpyrimidinylenes as nonpeptidic alpha-helical mimics.

A facile iterative synthesis of 2,5-terpyrimidinylenes that are structurally analogous to alpha-helix mimics is presented. Condensation of amidines with readily prepared alpha,beta-unsaturated alpha-cyanoketones gives 5-cyano-substituted pyrimidines. Iterative transformation of the 5-cyano group into an amidine allows synthesis of 2,5-terpyrimidinylenes with variable groups at the 4-, 4'-, and 4''-positions.

Efficient assembly of 2,5,6-substituted pyrimidines via MgI(2)-mediated Morita-Baylis-Hillman reaction.

A mild and efficient protocol for the synthesis of a 2,6-disubstituted pyrimidine-5-carboxylate library via a Morita-Baylis-Hillman (MBH) adduct is described. Herein, the three step methodology involves the use of substituted alpha-iodomethylene beta-keto ester intermediates obtained after oxidation of the MBH adducts, which are condensed with various types of amidine or guanidine derivatives, to generate the 2, 6-disubstituted pyrimidines-5-carboxylate libraries.

(S)-(Z)-Methyl 2-[2,3-bis-(benzyl-oxy-carbon-yl)guanidino]-4-methyl-penta-no-ate.

The title mol-ecule, C(24)H(29)N(3)O(6), has a nearly planar ten-atom C(3)N(3)O(4) core, on account of both N-H groups forming six-membered-ring intra-molecular hydrogen bonds to carbamate carbonyl O atoms. The absolute configuration was determined from resonant scattering of light atoms in Mo Kα radiation, agreeing with the configuration of starting materials.

Discovery of a novel proteasome inhibitor selective for cancer cells over non-transformed cells.

Numerous proteins controlling cell cycle progression, apoptosis and angiogenesis are degraded by the ubiquitin/proteasome system, which has become the subject for intense investigations for cancer therapeutics. Therefore, we used in silico and experimental approaches to screen compounds from the NCI chemical libraries for inhibitors against the chymotrypsin-like (CT-L) activity of the proteasome and discovered PI-083. Molecular docking indicates that PI-083 interacts with the Thr21, Gly47 and Ala49 residues of the beta5 subunit and Asp114 of the beta6 subunit of the proteasome.

Photophysical studies of the trans to cis isomerization of the push-pull molecule: 1-(pyridin-4-yl)-2-(N-methylpyrrol-2-yl)ethene (mepepy).

Organic molecules possessing intramolecular charge-transfer properties (D-pi-A type molecules) are of key interest particularly in the development of new optoelectronic materials as well as photoinduced magnetism. One such class of D-pi-A molecules that is of particular interest contains photoswitchable intramolecular charge-transfer states via a photoisomerizable pi-system linking the donor and acceptor groups. Here we report the photophysical and electronic properties of the trans to cis isomerization of 1-(pyridin-4-yl)-2-(N-methylpyrrol-2-yl)ethene ligand (mepepy) in aqueous solution using photoacoustic calorimetry (PAC) and theoretical methods.

Molecular docking/dynamics studies of Aurora A kinase inhibitors.

The binding modes of a known 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole, quinazoline, pyrimidine and indolinone series of Aurora A kinase inhibitors have been studied using molecular docking and molecular dynamics (MD) simulations. Crystallographic bound compound 8 was precisely predicted by our docking procedure as evident from 0.43A root mean square (rms) deviations.

The development of molecular clamps as drugs.

Some enzymes catalyze the modification of an ensemble of substrates in vivo and, as a consequence, are not ideal targets for active-site-directed drugs. One solution to inhibiting such multisubstrate enzymes would be a drug that binds tightly to only one substrate, which prevents the binding of that substrate to the enzyme. Ideally, such a drug (called a molecular clamp, a molecular forcep or a molecular tweezer) would prevent the enzymatic processing of only the targeted substrate.

Disordered syn-anti hydrogen-bonded chains in 3-(ferrocenylcarbonyl)propionic acid.

The title compound, [Fe(C(5)H(5))(C(9)H(9)O(3))], has Fe-centroid distances of 1.6551 (11) and 1.6445 (11) A to the cyclopentadienyl rings.

Fluorescence of cis-1-amino-2-(3-indolyl)cyclohexane-1-carboxylic acid: a single tryptophan chi(1) rotamer model.

A constrained derivative, cis-1-amino-2-(3-indolyl)cyclohexane-1-carboxylic acid, cis-W3, was designed to test the rotamer model of tryptophan photophysics. The conformational constraint enforces a single chi(1) conformation, analogous to the chi(1) = 60 degrees rotamer of tryptophan. The side-chain torsion angles in the X-ray structure of cis-W3 were chi(1) = 58.

Intramolecular quenching of tryptophan fluorescence by the peptide bond in cyclic hexapeptides.

Intramolecular quenching of tryptophan fluorescence by protein functional groups was studied in a series of rigid cyclic hexapeptides containing a single tryptophan. The solution structure of the canonical peptide c[D-PpYTFWF] (pY, phosphotyrosine) was determined in aqueous solution by 1D- and 2D-(1)H NMR techniques. The peptide backbone has a single predominant conformation.

Peptides with indirect in vivo activity against an intracellular pathogen: selective lysis of infected macrophages.

A collection of natural peptides, simplified analogs of natural peptides, de novo amphipathic peptides and de novo amphipathic peptides composed of 50-80% alpha,alpha-dialkylated glycines (alpha,alpha-Dags) were synthesized on solid-phase resin as the C-terminus amides using N-alpha-fluorenylmethyloxycarbonyl protection. The synthesis of the peptides rich in alpha,alpha-Dags used acid fluoride coupling methods. The peptides show antimicrobial activity against Escherichia coli and Staphylococcus aureus but no direct antimicrobial activity against Brucella abortus at 100 microm in vitro.