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Papers by fernando dela cruz

Bioorg Medicinal Chem Letter, 2006

A series of oxazole-substituted indanylacetic acids were prepared which show a spectrum of activi... more A series of oxazole-substituted indanylacetic acids were prepared which show a spectrum of activity as ligands for PPAR nuclear receptor subtypes.A series of substituted indanylacetic acids were prepared which showed a spectrum of agonist activity against PPAR nuclear receptor subtypes.

Bioorg Medicinal Chem Letter, 2007

A series of indane acetic acid derivatives were prepared which show a spectrum of activity as ins... more A series of indane acetic acid derivatives were prepared which show a spectrum of activity as insulin sensitizers and PPAR-α and PPAR-δ ligands. In vivo data are presented for insulin sensitizers with selectivity for PPAR-δ over PPAR-α.A novel series of indane acetic acid molecules are insulin sensitizers and have selectivity for PPAR-δ agonist activity over PPAR-α.

The Journal of Steroid Biochemistry and Molecular Biology, 1997

Transcriptional activation of the Drosophila ecdysone receptor (EcR) was studied in yeast cells, ... more Transcriptional activation of the Drosophila ecdysone receptor (EcR) was studied in yeast cells, which carry a reporter plasmid containing the ecdysone response element in the absence or presence of its heterodimeric partners, ultraspiracle protein (USP) or human retinoid X receptor (RXR~). High constitutive transcriptional activation was detected in the yeast strain expressing EcR, but not USP c,r RXR~ in the absence of ponasterone or muristerone A. Incubation of these ligands with yeast cells coexpressing EcR and USP or RXR~ did not enhance the constitutive transcriptional activity. However, specific Hgand binding using [3H]ponasterone A as a radioactive ligand was detected only in yeast extracts prepared from the yeast strain coexpressing EcR and USP, but not from yeast strains expressing only EcR or USP. The ligand binding characteristics of the EcR/USP complexes were similar to those reported in an insect cell line with a Kd value of 1.8 nM for [3H]ponasterone A. These data are in contrast to mammalian cell transfection studies, and indicate that the EcR is the only member of the nuclear receptor superfamily of ligand-activated transcription factors which functions as a constitutive transcriptional activator in yeast, although the EcR/USP complexes exhibit normal ligand binding properties.

Journal of Medicinal Chemistry, 2007

Aim: The increasing incidences of type 2 diabetes mellitus, represents a considerable public heal... more Aim: The increasing incidences of type 2 diabetes mellitus, represents a considerable public health problem and characterized by loss in sensitivity of tissues to insulin which can be restored by activation of Peroxisome Proliferator-Activated Receptors (PPARs). The present work takes in consideration for the development of PPAR agonists, which can activate PPARs and is expected to lower LDL cholesterol and triglycerides, raise HDL cholesterol and normalize hyperglycaemia. Materials and Methods: Quantitative Structure-Activity Relationship (QSAR) study is performed by means of Multiple Linear Regression (MLR) analysis on a set of indanyl acetic acid derivatives followed by ADMET prediction and Docking Studies. Results: A good correlation is found by regression analysis between the observed and predicted activities as evident by their R 2 (0.81), Q 2 (0.81) and R 2 pred (0.86) for PPARα and R 2 (0.66), Q 2 (0.66) and R 2 pred (0.90) for PPARδ and R 2 (0.82), Q 2 (0.77) and R 2 pred (0.58) for PPARγ respectively. Molecular docking of the ligands qualifying all the Drug Likeness properties to the proteins PPARα (PDB ID: 3ET1), PPARδ (PDB ID: 3ET2) and PPARγ (PDB ID: 3ET3) with FlexX score-11.98,-9.69 and-21.48 respectively followed by core hoping. Conclusion: Docking studies revealed that hydrogen-bonding interactions are crucial for the binding of ligands with the target. Core replacement of the best-docked conformations of the selected ligand is performed in order to obtain more potent and novel ligands.

Journal of Biological Chemistry, 2003

Pituitary adenylate cyclase-activating peptide (PACAP) has a specific receptor PAC1 and shares tw... more Pituitary adenylate cyclase-activating peptide (PACAP) has a specific receptor PAC1 and shares two receptors VPAC1 and VPAC2 with vasoactive intestinal peptide (VIP). VPAC2 activation enhances glucose-induced insulin release while VPAC1 activation elevates glucose output. To generate a large pool of VPAC2 selective agonists for the treatment of type 2 diabetes, structure-activity relationship studies were performed on PACAP, VIP, and a VPAC2 selective VIP analog. Chemical modifications on this analog that prevent recombinant expression were sequentially removed to show that a recombinant peptide would retain VPAC2 selectivity. An efficient recombinant expression system was then developed to produce and screen hundreds of mutant peptides. The 11 mutations found on the VIP analog were systematically replaced with VIP or PACAP sequences. Three of these mutations, V19A, L27K, and N28K, were sufficient to provide most of the VPAC2 selectivity. C-terminal extension with the KRY sequence from PACAP38 led to potent VPAC2 agonists with improved selectivity (100-1000-fold). Saturation mutagenesis at positions 19, 27, 29, and 30 of VIP and chargescanning mutagenesis of PACAP27 generated additional VPAC2 selective agonists. We have generated the first set of recombinant VPAC2 selective agonists described, which exhibit activity profiles that suggest therapeutic utility in the treatment of diabetes.

Environmental Health Perspectives, 1999

Endocrine disruptors are hormone mimics that modify hormonal action in humans and animals. It is ... more Endocrine disruptors are hormone mimics that modify hormonal action in humans and animals. It is thought that some endocrine disruptors modify estrogen and androgen action in humans and animals by suppressing aromatase activity. Aromatase cytochrome P450 is the key enzyme that converts C19 androgens to aromatic C18 estrogenic steroids. We have developed a novel aromatase inhibitor screening method that allows us to identify antiaromatase activity of various environmental chemicals. The screen was developed by coexpressing the human aromatase and the mouse androenrceptor in yeast ceals, which carry the androgen-responsive ,B-galactosidase reporter plasmid. Functional expression of aromatase in yast has been donstrated using the PHI-water release assay with intact cells as well as with yeast microsomes. The aromatase activity could be blocked by known aromatase inhibitors such as aminogluhimide (AG). Yeast-produced androgen receptors were able to transactivate a yeast baal promoter linked to an androgenresponsive element in response to androgens. The resultant triple yea transformant responde to the treatment of testosterone, androstenedione, or 5a-dihydrotesosterone (5a-DHT). In the absence of the aromatase inhibitor AG, transcriptional activation was observed only for the nonaromatizable androgen 5a-DHT. However, the two aromatizable androgens (testosterone and androstenedione) induced the reporter activity in the presence ofAG. Using this yeast-based. assay, we confirmed that two &favones, chrysin and an ahtholflone, are inhibitors ofaromatase. Thus, this yeast system allows us to develop a high-throughput screening method, without using radioactiv substrate, to identify aromatase inhibitors as well as new ligands (nonaromatizable androgen mimics) for the androgen receptors. In addition, this mehod also allows us to distnguish nonandrogenic aromatase inhibitors from inhibitors with androgenic activity. This yeast screening method will be useful to screen environmental cemicals for their antiaromatase activity and for their interaction with androgen receptor.

Diabetes, 2002

Pituitary adenylate cyclase—activating peptide (PACAP) and vasoactive intestinal peptide (VIP) ac... more Pituitary adenylate cyclase—activating peptide (PACAP) and vasoactive intestinal peptide (VIP) activate two shared receptors, VPAC1 and VPAC2. Activation of VPAC1 has been implicated in elevating glucose output, whereas activation of VPAC2 may be involved in insulin secretion. A hypothesis that a VPAC2-selective agonist would enhance glucose disposal by stimulating insulin secretion without causing increased hepatic glucose production was tested using a novel selective agonist of VPAC2. This agonist, BAY 55-9837, was generated through site-directed mutagenesis based on sequence alignments of PACAP, VIP, and related analogs. The peptide bound to VPAC2 with a dissociation constant (Kd) of 0.65 nmol/l and displayed >100-fold selectivity over VPAC1. BAY 55-9837 stimulated glucose-dependent insulin secretion in isolated rat and human pancreatic islets, increased insulin synthesis in purified rat islets, and caused a dose-dependent increase in plasma insulin levels in fasted rats, with...

Bioorganic & Medicinal Chemistry Letters, 2007

A series of indane acetic acid derivatives were prepared which show a spectrum of activity as ins... more A series of indane acetic acid derivatives were prepared which show a spectrum of activity as insulin sensitizers and PPAR-a and PPAR-d ligands. In vivo data are presented for insulin sensitizers with selectivity for PPAR-d over PPAR-a.

Bioorganic & Medicinal Chemistry Letters, 2006