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Biomedical subjects

A Richard Chamberlin

Publications and source records attributed to A Richard Chamberlin.

18 recordsLinked to original sources
PubMed2006

Design, synthesis, and biological evaluation of chicoric acid analogs as inhibitors of HIV-1 integrase.

A series of analogs of the potent HIV-1 integrase (HIV IN) inhibitor chicoric acid (CA) was designed with the intention of ameliorating some of the parent natural product's undesirable properties, in particular its toxicity, instability, and poor membrane permeability. More than 70 analogs were synthesized and assayed for three types of activity: (1) the ability to inhibit 3'-end processing and strand transfer reactions using recombinant HIV IN in vitro, (2) toxicity against the CD4+ lymphoblastoid cell line, MT2, and (3) anti-HIV activity against HIV(LAI). CA analogs lacking one of the carboxyl groups of CA and with 3,4,5-trihydroxycinnamoyl sidechains in place of the caffeoyl group of CA exhibited the most potent inhibition of HIV replication and end-processing activity. Galloyl-substituted derivatives also displayed very potent in vitro and in vivo activities, in most cases exceeding the inhibitory effects of CA itself. Conversely, analogous monocarboxy caffeoyl analogs exhibited only modest inhibition, while the corresponding 3,4-dihydroxybenzoyl-substituted compounds were devoid of activity.

Anti-HIV Agents↗
PubMed2006

Pharmacophore identification: the case of the ser/thr protein phosphatase inhibitors.

This review provides a chronological account of the identification and refinement of the pharmacophore for inhibition of two key serine/threonine protein phosphatases, PP1 and PP2A. The dramatic impact of natural product isolation, molecular modeling, analogue design, biochemical studies, and crystallography on the evolution of the pharmacophore will be described.

Enzyme Inhibitors↗
PubMed2005

The substituted aspartate analogue L-beta-threo-benzyl-aspartate preferentially inhibits the neuronal excitatory amino acid transporter EAAT3.

The excitatory amino acid transporters (EAATs) play key roles in the regulation of CNS L-glutamate, especially related to synthesis, signal termination, synaptic spillover, and excitotoxic protection. Inhibitors available to delineate EAAT pharmacology and function are essentially limited to those that non-selectively block all EAATs or those that exhibit a substantial preference for EAAT2. Thus, it is difficult to selectively study the other subtypes, particularly EAAT1 and EAAT3. Structure activity studies on a series of beta-substituted aspartate analogues identify L-beta-benzyl-aspartate (L-beta-BA) as among the first blockers that potently and preferentially inhibits the neuronal EAAT3 subtype. Kinetic analysis of D-[(3)H]aspartate uptake into C17.2 cells expressing the hEAATs demonstrate that L-beta-threo-BA is the more potent diastereomer, acts competitively, and exhibits a 10-fold preference for EAAT3 compared to EAAT1 and EAAT2. Electrophysiological recordings of EAAT-mediated currents in Xenopus oocytes identify L-beta-BA as a non-substrate inhibitor. Analyzing L-beta-threo-BA within the context of a novel EAAT2 pharmacophore model suggests: (1) a highly conserved positioning of the electrostatic carboxyl and amino groups; (2) nearby regions that accommodate select structural modifications (cyclopropyl rings, methyl groups, oxygen atoms); and (3) a unique region L-beta-threo-BA occupied by the benzyl moieties of L-TBOA, L-beta-threo-BA and related analogues. It is plausible that the preference of L-beta-threo-BA and L-TBOA for EAAT3 and EAAT2, respectively, could reside in the latter two pharmacophore regions.

Amino Acid Transport System X-AG↗
PubMed2005

Indole- and indoline-based kainate analogues with antagonist activity at ionotropic glutamate receptors.

A conformationally constrained, indole-based kainate analogue was designed based on Gouaux's X-ray structure of kainic acid bound to an iGluR2(S1S2) construct, a structural model for AMPA/kainate ionotropic glutamate receptors. In contrast to the parent kainic acid, a potent agonist, this compound, along with three structurally related analogues derived from synthetic intermediates, exhibited antagonist behavior towards KAR expressed in oocytes, a result that is rationalized by molecular modeling studies.

Animals↗
PubMed2005

Fluorescent profiling of natural product producers.

The identification of natural product producer organisms remains a problem for both isolation and natural product classification. A concise screen is developed through fluorescent modification of a set of natural products that offer a common activity. Through real-time multicolor microscopy, the processing, storage, and effects of a natural product are rapidly screened at the level of the strain and individual organism.

Animals↗
PubMed2004

Modified norcantharidins; synthesis, protein phosphatases 1 and 2A inhibition, and anticancer activity.

Fourteen modified norcantharidin analogues have been synthesised and screened for their ability to inhibit the serine/threonine protein phosphatases 1 and 2A. The most potent compounds found were 10 (PP1 IC(50)=13+/-5 microM; PP2A IC(50)=7+/-3 microM) and 16 (PP1 IC(50)=18+/-8 microM; PP2A IC(50)=3.2+/-0.4 microM). Overall, only analogues possessing at least one acidic residue at the former anhydride warhead displayed any PP1 or PP2A inhibitory action. The ability of these analogues to inhibit PP1 and PP2A correlates well with their observed anti-cancer activity against a panel of five cancer cell lines: A2780 (human ovarian carcinoma), G401 (human kidney carcinoma), HT29 (human colorectal carcinoma), H460 (human lung carcinoma) and L1210 (murine leukemia).

Animals↗
PubMed2003

Microcystin analogues comprised only of Adda and a single additional amino acid retain moderate activity as PP1/PP2A inhibitors.

A series of greatly simplified microcystin analogues comprised only of Adda (the beta-amino acid common to the microcystins, nodularins, and motuporin,) and a single additional amino acid residue was synthesized and screened for inhibition of the protein phosphatases 1 and 2A. Several of the analogues were shown to be mid-nanomolar inhibitors of the enzymes.

Amino Acids↗
PubMed2003

Linearized and truncated microcystin analogues as inhibitors of protein phosphatases 1 and 2A.

A series of acyclic, truncated microcystin analogues, comprised of the dienic beta-amino acid (Adda) and up to four additional amino acids characteristic of the parent toxin, was synthesized and screened for activity as inhibitors of PP1 and PP2A. Despite a recent report to the contrary for a microcystin-derived tetrapeptide degradation product, none approaches the potency of microcystin itself.

Bacterial Toxins↗
PubMed2003

The selective inhibition of phosphatases by natural toxins: the anhydride domain of tautomycin is not a primary factor in controlling PP1/PP2A selectivity.

Analogues of the potent and moderately selective PP1/PP2A inhibitor tautomycin (TM) were prepared with modifications in the C1'-C7' anhydride moiety. While all retain varying degrees of activity within a 3000-fold range of potencies, they also show remarkable constancy in their IC(50) ratios, suggesting that the anhydride moiety is not critical in controlling the selectivity of inhibition.

Anhydrides↗
PubMed2003

A new model of the tautomycin-PP1 complex that is not analogous to the corresponding okadaic acid structure.

A revised model of PP1-tautomycin (TM) complex suggests that this toxin does not bind in a conformation analogous to its structural cousin okadaic acid (OA), as has been assumed, but instead more resembles the mode of binding adopted by calyculin. This model rationalizes the unexpected potency of a truncated TM analogue lacking the bicyclic ketal common to TM and OA.

Enzyme Inhibitors↗
PubMed2002

Rapid solid-phase synthesis of DNA-binding pyrrole-imidazole polyamides.

Pyrrole-imidazole polyamides can be synthesized to target predetermined sequences of DNA with nanomolar affinity and high specificity, and have been shown to modulate gene transcription both in vitro and in vivo. To make polyamides more readily available to biological laboratories, we have developed a rapid solid-phase synthesis based on azabenzotriazole (OAt) activation that decreases synthesis time 60% compared to standard benzotriazole (OBt) techniques, without loss of yield or purity.

DNA↗
PubMed2002

Total synthesis of dysiherbaine.

A convergent total synthesis of the marine natural product dysiherbaine was accomplished. The key steps of the synthesis are an alkylation at the gamma-carbon of a protected glutamate with a highly substituted pyran derived from mannose, which was followed by a ring-contraction cascade reaction, which simultaneously gave the tetrasubstituted carbon and the hexahydrofuro[3,2-b]pyran ring system of the natural product.

Alanine↗
PubMed2002

5'-alkyl-benzothiadiazides: a new subgroup of AMPA receptor modulators with improved affinity.

AMPA receptors form a major subdivision of the glutamate receptor family that mediates excitatory synaptic transmission in the brain. Currents through AMPA receptors can be up- or down-regulated by compounds that allosterically modulate receptor kinetics through binding sites distinct from that for glutamate. One of those modulators is the benzothiadiazide IDRA-21 which has been reported to enhance synaptic transmission and be effective in behavioral tests, but typically requires threshold concentrations of at least 100 microM to be active in vitro. In this study, new benzothiadiazides were developed with IDRA-21 as lead compound and examined for their potency in modulating AMPA receptor kinetics. A significant increase in drug affinity was obtained by alkyl substitution at the 5'-position of IDRA-21; substitutions at other positions of the benzothiadiazide core generally did not yield a further gain in affinity and in some cases abolished drug binding. The 5'-ethyl derivative exhibited an EC(50) value in the order of 22 microM which represents about a 30-fold gain in affinity over that of IDRA-21. The EC(50) value is comparable to that of cyclothiazide, the most potent benzothiadiazide drug, but the effects on AMPA receptors differed substantially between these two compounds in that the 5'-ethyl derivative of IDRA-21 greatly increased the binding affinity for receptor agonists whereas cyclothiazide is known to reduce agonist binding. The structure--activity relationships reported here thus offer to provide new insights how receptor kinetics is linked to particular aspects of receptor--drug interactions.

Animals↗