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Biomedical subjects

Murray Goodman

Publications and source records attributed to Murray Goodman.

At least 19 recordsLinked to original sources
PubMed2006

Cancer-related bone pain is attenuated by a systemically available delta-opioid receptor agonist.

Patients with bone cancer report severe pain and receive mu-opioids. We developed a family of peptidomimetic delta-agonists, one of which H2N-Tyr-dVal-Gly-Phe-Ala-OH ([dVal(L)2,Ala(L)5]E) binds with a 1700x affinity at the delta versus mu receptor. To examine the systemic analgesic efficacy of this delta-agonist versus morphine in osteosarcoma pain, osteosarcoma cells are injected into one femur of the anesthetized mouse. After 10-18 days, a decalcification of the injected femur occurs along with a pronounced tactile allodynia. IP morphine and [dVal(L)2,Ala(L)5]E produced a dose-dependent reversal of allodynia with the respective ED50 values being 5.3+/-1.9 mg/kg for morphine and 1.3+/-0.3 mg/kg for [dVal(L)2,Ala(L)5]E. Plotting peak effect versus area under the analgesic curve for doses of morphine and [dVal(L)2,Ala(L)5]E revealed overlapping curves suggesting that for a given effect, [dVal(L)2,Ala(L)5]E produced a similar duration of action as morphine. These effects were reversed by IP naloxone (3 mg/kg). IP naltrindole (1 mg/kg) preferentially reversed [dVal(L)2,Ala(L)5]E. The upper dose effects of morphine but not [dVal(L)2,Ala(L)5]E were limited by pronounced hyperactivity. No other effects were noted. These results show that IP [dVal(L)2,Ala(L)5]E through a delta receptor produces analgesia equal in efficacy to that of morphine but with a 4.5-fold greater potency. Over the doses examined, morphine actions were side effect limited. The delta side effects were not so limited, suggesting a favorable therapeutic ratio for delta-agonists in this pain model. These studies suggest that a systemically delivered delta-opioid agonist has pronounced analgesic properties on a preclinical cancer pain model.

Analgesics↗
PubMed2006

Fe(III)-binding collagen mimetics.

The synthesis and characterization of hydroxamic acid containing single-chain and TRIS-assembled (where TRIS is tris(carboxyethoxymethyl)aminomethane) collagen mimetics are reported. We have engineered an Fe(III)-binding domain by placing a hydroxamic acid group at the C termini of collagen mimetic chains composed of the Gly-Pro-NLeu sequence. The circular dichroism spectra and thermal denaturation studies show an enhancement in triple-helical thermal stability upon the addition of Fe(III) for the TRIS-assembled structure. No triple-helical structure was detected for the single-chain collagen mimetic. From the absorbance shown in the UV-vis spectra, we believe that the thermal stabilization of the triple helix is the direct result of a coordination complex between Fe(III) and the hydroxamate groups tethered to the C termini of the collagen mimetic peptide chains.

Binding Sites↗
PubMed2006

Conformation analysis of aspartame-based sweeteners by NMR spectroscopy, molecular dynamics simulations, and X-ray diffraction studies.

We report here the synthesis and the conformation analysis by 1H NMR spectroscopy and computer simulations of six potent sweet molecules, N-[3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl]-alpha-L-aspartyl-S-tert-butyl-L-cysteine 1-methylester (1; 70 000 times more potent than sucrose), N-[3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl]-alpha-L-aspartyl-beta-cyclohexyl-L-alanine 1-methylester (2; 50 000 times more potent than sucrose), N-[3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl]-alpha-L-aspartyl-4-cyan-L-phenylalanine 1-methylester (3; 2 000 times more potent than sucrose), N-[3,3-dimethylbutyl]-alpha-L-aspartyl-(1R,2S,4S)-1-methyl-2-hydroxy-4-phenylhexylamide (4; 5500 times more potent than sucrose), N-[3-(3-hydroxy-4-methoxyphenyl)propyl]-alpha-L-aspartyl-(1R,2S,4S)-1-methyl-2-hydroxy-4-phenylhexylamide (5; 15 000 times more potent than sucrose), and N-[3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl]-alpha-L-aspartyl-(1R,2S,4S)-1-methyl-2-hydroxy-4-phenylhexylamide (6; 15 000 times more potent than sucrose). The "L-shaped" structure, which we believe to be responsible for sweet taste, is accessible to all six molecules in solution. This structure is characterized by a zwitterionic ring formed by the AH- and B-containing moieties located along the +y axis and by the hydrophobic group X pointing into the +x axis. Extended conformations with the AH- and B-containing moieties along the +y axis and the hydrophobic group X pointing into the -y axis were observed for all six sweeteners. For compound 5, the crystal-state conformation was also determined by an X-ray diffraction study. The result indicates that compound 5 adopts an L-shaped structure even in the crystalline state. The extraordinary potency of the N-arylalkylated or N-alkylated compounds 1-6, as compared with that of the unsubstituted aspartame-based sweet taste ligands, can be explained by the effect of a second hydrophobic binding domain in addition to interactions arising from the L-shaped structure. In our examination of the unexplored D zone of the Tinti-Nofre model, we discovered a sweet-potency-enhancing effect of arylalkyl substitution on dipeptide ligands, which reveals the importance of hydrophobic (aromatic)-hydrophobic (aromatic) interactions in maintaining high potency.

Aspartame↗
PubMed2005

Discovery of iodinated somatostatin analogues selective for hsst2 and hsst5 with excellent inhibition of growth hormone and prolactin release from rat pituitary cells.

Inhibition of growth hormone (GH) and prolactin (PRL) release from the anterior pituitary gland is mediated through somatostatin receptor subtypes sst2 and sst5. It has been found that somatostatin (SS) analogues that are selective for both receptor subtypes are more effective at inhibiting GH and PRL release than monospecific analogues alone. We synthesized several disulfide-bridged octapeptide SS analogues. Iodinated compounds 7, (4-amino-3-iodo)-d-Phe-c[Cys-Tyr-d-Trp-Lys-Val-Cys]-Thr-NH2, and 9, (4-amino-3-iodo)-d-Phe-c[Cys-(3-iodo)-Tyr-d-Trp-Lys-Val-Cys]-Thr-NH2, were as potent as somatostatin in binding at receptors hsst2 and hsst5 and inhibited GH and PRL release from rat pituitary cells as potently as somatostatin.

2,2'-Dipyridyl↗
PubMed2005

Utilizing the intramolecular Fukuyama-Mitsunobu reaction for a flexible synthesis of novel heterocyclic scaffolds for peptidomimetic drug design.

We report the synthesis of the novel scaffolds pyrazino[1,2-b]isoquinoline and pyrrolo[1,2-a]pyrazine displaying the somatostatin pharmacophores. Both classes of compounds contain a pyrazine heterocycle, which can be prepared in a straightforward manner utilizing an intramolecular Fukuyama-Mitsunobu reaction. As both the families derive from amino acids, they can be accessed in high optical purity.

Amino Acids↗
PubMed2005

Intracellular localization and trafficking of fluorescein-labeled cisplatin in human ovarian carcinoma cells.

PURPOSE: We sought to identify the subcellular compartments in which cisplatin [cis-diamminedichloroplatinum (DDP)] accumulates in human ovarian carcinoma cells and define its export pathways. EXPERIMENTAL DESIGN: Deconvoluting digital microscopy was used to identify the subcellular location of fluorescein-labeled DDP (F-DDP) in 2008 ovarian carcinoma cells stained with organelle-specific markers. Drugs that block vesicle movement were used to map the traffic pattern. RESULTS: F-DDP accumulated in vesicles and were not detectable in the cytoplasm. F-DDP accumulated in the Golgi, in vesicles belonging to the secretory export pathway, and in lysosomes but not in early endosomes. F-DDP extensively colocalized with vesicles expressing the copper efflux protein, ATP7A, whose expression modulates the cellular pharmacology of DDP. Inhibition of vesicle trafficking with brefeldin A, wortmannin, or H89 increased the F-DDP content of vesicles associated with the pre-Golgi compartments and blocked the loading of F-DDP into vesicles of the secretory pathway. The importance of the secretory pathway was confirmed by showing that wortmannin and H89 increased whole cell accumulation of native DDP. CONCLUSIONS: F-DDP is extensively sequestered into vesicular structures of the lysosomal, Golgi, and secretory compartments. Much of the distribution to other compartments occurs via vesicle trafficking. F-DDP detection in the vesicles of the secretory pathway is consistent with a major role for this pathway in the efflux of F-DDP and DDP from the cell.

Adenosine Triphosphatases↗
PubMed2004

An efficient RCM-based synthesis of orthogonally protected meso-DAP and FK565.

A condensation--ring-close--ring-open sequence was employed for the synthesis of orthogonally protected meso-2,6-diaminopimelic acid, starting from easily accessible chiral synthons. Condensation of suitably protected L-allylglycine and D-vinylglycinol derivatives was followed by Grubbs' ring-closing metathesis to generate the key lactam intermediate. This strategy has been applied to a concise total synthesis of the potent immunostimulatory peptide FK565.

Cyclization↗
PubMed2004

Metal-assisted assembly and stabilization of collagen-like triple helices.

Single-chain and TRIS-assembled collagen mimetic peptide structures incorporating catechol groups were synthesized. When 1/3 equiv of Fe3+ was added to the single-chain compound in 50 mM CAPS buffer (pH 10), the 1:3 Fe3+-catechol complex that formed acted as an N-terminal scaffold to assemble the triple helix. When 1 equiv of Fe3+ was added to the TRIS-assembled compound in the buffer solution, the Fe3+-catechol complex acted as an extra C-terminal scaffold, which lead to a triple helix with both termini tethered. The formation of this C-terminal complex increased the Tm by a remarkable 22 degrees C!

Catechols↗
PubMed2004

Increased expression of the copper efflux transporter ATP7A mediates resistance to cisplatin, carboplatin, and oxaliplatin in ovarian cancer cells.

PURPOSE: The goal of this study was to determine the effect of small changes in ATP7A expression on the pharmacodynamics of cisplatin, carboplatin, and oxaliplatin in human ovarian carcinoma cells. EXPERIMENTAL DESIGN: Drug sensitivity and cellular pharmacology parameters were determined in human 2008 ovarian carcinoma cells and a subline transfected with an ATP7A-expression vector ATP7A (2008/MNK). Drug sensitivity was determined by clonogenic assay, platinum (Pt) levels were measured by inductively coupled plasma mass spectroscopy, copper (Cu) accumulation was quantified with (64)Cu, and the subcellular distribution of ATP7A was assessed by confocal digital microscopy. RESULTS: The 1.5-fold higher expression of ATP7A in the 2008/MNK cells was sufficient to alter Cu cellular pharmacokinetics but not confer Cu resistance. In contrast, it was sufficient to render the 2008/MNK cells resistant to cisplatin, carboplatin, and oxaliplatin. Resistance was associated with increased rather than decreased whole-cell Pt drug accumulation and increased sequestration of Pt into the vesicular fraction. Cu triggered relocalization of ATP7A away from the perinuclear region, whereas at equitoxic concentrations the Pt drugs did not. CONCLUSIONS: A small increase in ATP7A expression produced resistance to all three of the clinically available Pt drugs. Whereas increased expression of ATP7A reduced Cu accumulation, it did not reduce accumulation of the Pt drugs. Under conditions where Cu triggered ATP7A relocalization, the Pt drugs did not. Thus, although ATP7A is an important determinant of sensitivity to the Pt drugs, there are substantial differences between Cu and the Pt drugs with respect to how they interact with ATP7A and the mechanism by which ATP7A protects the cell.

Adenosine Triphosphatases↗
PubMed2004

Confocal microscopic analysis of the interaction between cisplatin and the copper transporter ATP7B in human ovarian carcinoma cells.

Some cisplatin (DDP)-resistant cells overexpress the copper export transporter ATP7B, and cells molecularly engineered to overexpress ATP7B are resistant to DDP. The interaction of Cu with ATP7B normally triggers its relocalization from the perinuclear region to more peripheral vesicles. To investigate the interaction of DDP with ATP7B, we examined the effect of DDP on the subcellular localization of ATP7B using human ovarian carcinoma cells expressing a cyan fluorescent protein (ECFP)-tagged ATP7B (2008/ECFP-ATP7B). ATP7B expression was confirmed in 2008/ECFP-ATP7B cells by Western blotting, and its functionality was documented by showing that it rendered the cells 1.9-fold resistant to CuSO(4) and 4.1-fold resistant to DDP and also reduced the accumulation of both drugs. There was greater sequestration of Pt into intracellular vesicles in the 2008/ECFP-ATP7B cells than in the 2008/ECFP cells. Confocal digital microscopy revealed that ECFP-ATP7B localized in the perinuclear region in absence of drug exposure and that both Cu and DDP triggered relocalization to more peripheral vesicular structures. A fluorescein-labeled form of DDP that retained cytotoxicity and was subject to the same mechanisms of resistance as DDP colocalized with ECFP-ATP7B in the 2008/ECFP-ATP7B cells, whereas the same fluorochrome lacking the DDP moiety did not. These results provide evidence that DDP directly interacts with ATP7B to trigger its relocalization and that ATP7B mediates resistance to DDP by sequestering it into vesicles of the secretory pathway for export from the cell.

Adenosine Triphosphatases↗
PubMed2004

Dendritic oligoguanidines as intracellular translocators.

A series of polyguanidylated dendritic structures that can be used as molecular translocators have been designed and synthesized based on nonpeptide units. The dendritic oligoguanidines conjugated with fluorescein or with a green fluorescent protein (GFP) mutant as cargos were isolated and characterized. Quantification and time-course analyses of the cellular uptake of the conjugates using HeLa S3 and human cervical carcinoma cells reveal that the polyguanidylated dendrimers have comparable translocation efficiency to the Tat(49-57) peptide. Furthermore, the deconvolution microscopy image analysis shows that they are located inside the cells. These results clearly show that nonlinear, branched dendritic oligoguanidines are capable of translocation through the cell membrane. This work also demonstrates the potential of these nonpeptidic dendritic oligoguanidines as carriers for intracellular delivery of small molecule drugs, bioactive peptides, and proteins.

Biopolymers↗
PubMed2003

Synthesis of 2-amino-4-pyrimidinones from resin-bound guanidines prepared using bis(allyloxycarbonyl)-protected triflylguanidine.

We have synthesized novel heterocyclic compounds from resin-bound guanidines. For this purpose, an amine immobilized on a solid support was acylated with protected amino acids. Following the deprotection, the liberated amines were guanidinylated utilizing a new member of the family of diurethane-protected triflyl guanidine reagents, N,N'-bis(allyloxycarbonyl)-N' '-triflylguanidine. The deprotected guanidines were subsequently regioselectively cyclized with beta-keto esters yielding novel compounds containing heterocyclic structures in high purities.

Amines↗
PubMed2003

Structure-activity relationships of dynorphin a analogues modified in the address sequence.

The peptide [Pro3]Dyn A(1-11)-NH2 2 exhibits high affinity (K(i) = 2.4 nM) and over 2000-fold selectivity for the opioid receptor. Stepwise removal of the C-terminal residues from this ligand demonstrated that its positively charged Arg residues, particularly Arg6 and Arg7, were crucial for binding to the kappa receptor. Analogues shorter than seven amino acids lacked significant affinity for opioid receptors. Comparison with a series of truncated analogues of Dyn A showed that the relative losses in binding potency differed only slightly between the two series. The neutral residues Ile8 and Pro10 could be removed without significant loss in affinity for the kappa receptor. Their replacement, in the Pro3 analogue, with additional Arg residues led to analogues with improved kappa affinity (e.g., [Pro3,Arg8]Dyn A(1-11)-NH2 20: K(i)(kappa) = 0.44 nM). This type of modification did not compromise the high kappa selectivity of the Pro3 analogues. These findings support the view that a negatively charged domain in the putative second extracellular loop of the kappa receptor selectively recognizes residues 6-11 of dynorphin through electrostatic interactions. As with parent compound 2, analogue 20 and related compounds displayed kappa antagonist properties.

Analgesics, Opioid↗
PubMed2003

Asymmetric hydrogenations for the synthesis of Boc-protected 4-alkylprolinols and prolines.

The utility of 4-substituted prolinols and their corresponding prolines in peptides, peptidomimetics, and natural products has motivated researchers to find new and efficient routes for their preparation. Herein, we report a general approach to the synthesis of Boc-protected 4-alkylprolinols and prolines via a divergent asymmetric hydrogenation strategy. Intermediate exocyclic olefins were prepared by Wittig-type reactions with ketone 6 and subjected to hydroxyl and sterically directed reductions. The Crabtree catalyst (Ir[COD]PyPCy(3)PF(6)) proved to be highly effective in diastereoselective hydrogenations to give trans-substituted pyrrolidines (9). Good facial selectivities were also observed in heterogeneous hydrogenations with Raney-nickel to obtain cis-substituted pyrrolidines (11). Employing this strategy, we describe the synthesis of novel prolinol and proline-based building blocks for incorporation into biologically relevant peptidomimetics.

Alkylation↗
PubMed2003

Structure-activity relationships of dynorphin analogs substituted in positions 2 and 3.

Following up on the observation that the dynorphin analog [Pro(3)]Dyn A(1-11)-NH(2) 2 possesses high affinity and selectivity for the kappa opioid receptor, a number of related peptides were prepared and characterized by radioligand binding and [(35)S]GTPgammaS assays. While incorporation of 2-azetidine carboxylic acid in position 3 led to the equally potent analog 3, the corresponding analog containing piperidine-2-carboxylic acid showed a nearly 90-fold reduction in kappa affinity. Differential preferred bond angles phi in the three building blocks might account for these observations. Compounds 2 and 3 were kappa antagonists with IC(50) values of 380 and 350 nM, respectively. The Sar(3) analog 7 and the Sar(2) analog 8 were kappa agonists, with greater selectivity than Dyn A(1-11)-NH(2) 1. In view of their high kappa affinities (8: K(i) = 1.5 nM; 2: K(i) = 2.4 nM), the new analogs were surprisingly weak kappa agonists or antagonists, e.g., the EC(50) value for the agonist 8 was 280 nM. Different kappa receptor subtypes in binding vs functional assays can not account for these results, since both assays were performed using the same membrane preparation.

Amino Acid Sequence↗