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author:("Zhu, yangyi")
1.  Lead Optimization of Anti-Malarial Propafenone Analogs 
Journal of medicinal chemistry  2012;55(13):6087-6093.
Previously reported studies identified analogs of propafenone that had potent antimalarial activity, reduced cardiac ion channel activity, and properties that suggested the potential for clinical development for malaria. Careful examination of the bioavailability, pharmacokinetics, toxicology, and efficacy of this series of compounds using rodent models revealed orally bioavailable compounds that are non-toxic and suppress parasitemia in vivo. Although these compounds possess potential for further preclinical development, they also carry some significant challenges.
PMCID: PMC4408918  PMID: 22708838
propafenone; malaria; MTD; PK; CYP inhibition; hERG
2.  Pharmacokinetics and Efficacy of the Spleen Tyrosine Kinase Inhibitor R406 after Ocular Delivery for Retinoblastoma 
Pharmaceutical Research  2014;31(11):3060-3072.
Retinoblastoma is a childhood cancer of the retina. Clinical trials have shown that local delivery of broad spectrum chemotherapeutic agents is efficacious. Recent studies characterizing the genomic and epigenomic landscape of retinoblastoma identified spleen tyrosine kinase (SYK) as a promising candidate for targeted therapy. The purpose of this study was to conduct preclinical testing of the SYK antagonist R406 to evaluate it as a candidate for retinoblastoma treatment.
The efficacy of the SYK antagonist R406 delivered locally in a human orthotopic xenograft mouse model of retinoblastoma was tested. Intraocular exposure of R406 was determined for various routes and formulations.
There was no evidence of efficacy for subconjunctival. R406. Maximal vitreal concentration was 10-fold lower than the minimal concentration required to kill retinoblastoma cells in vitro. Dosage of R406 subconjunctivally from emulsion or suspension formulations, direct intravitreal injection of the soluble prodrug of R406 (R788), and repeated topical administration of R406 all increased vitreal exposure, but failed to reach the exposure required for retinoblastoma cell death in culture.
Taken together, these data suggest that R406 is not a viable clinical candidate for the treatment of retinoblastoma. This study highlights the importance of pharmacokinetic testing of molecular targeted retinoblastoma therapeutics.
Electronic supplementary material
The online version of this article (doi:10.1007/s11095-014-1399-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4213378  PMID: 24906597
Ocular drug delivery; R406; Retinoblastoma; Spleen tyrosine kinase
3.  Synthesis and evaluation of 7-substituted 4-aminoquinoline analogs for antimalarial activity 
Journal of medicinal chemistry  2011;54(20):7084-7093.
We previously reported that substituted 4-aminoquinolines with a phenylether substituent at the 7-position of the quinoline ring and the capability of intramolecular hydrogen bonding between the protonated amine on the side chain and a hydrogen bond acceptor on the amine’s alkyl substituents exhibited potent antimalarial activity against the multi-drug resistant strain P. falciparum W2. We employed a parallel synthetic method to generate diaryl ether, biaryl, and alkylaryl 4-aminoquinoline analogs, in the background of a limited number of side chain variations that had previously afforded potent 4-aminoquinolines. All subsets were evaluated for their antimalarial activity against the chloroquine-sensitive strain 3D7 and the chloroquine-resistant K1 and cytotoxicity mammalian cell lines. While all three arrays showed good antimalarial activity, only the biaryl-containing subset showed consistently good potency against the drug-resistant K1strain good selectivity with regard to mammalian cytotoxicity. Overall, our data indicate that the biaryl-containing series contains promising candidates for further study.
PMCID: PMC3697074  PMID: 21910466
4.  Synthesis and evaluation of sulfonylnitrophenylthiazoles (SNPT's) as thyroid hormone receptor-coactivator interaction inhibitors 
Journal of Medicinal Chemistry  2012;55(5):2301-2310.
We previously identified a series of methylsulfonylnitrobenzoates (MSNB's) that block the interaction of the thyroid hormone receptor with its coactivators. MSNB's inhibits coactivator binding through irreversibly modifying cysteine 298 of thyroid hormone receptor (TR). Although MSNB's have better pharmacological features than our first generation inhibitors (β-aminoketones) they contain a potentially unstable ester linkage. Here we report the bioisosteric replacement of the ester linkage with a thiazole moiety, yielding sulfonylnitrophenylthiazoles (SNPT's). An array of SNPT's representing optimal side chains from the MSNB series was constructed using parallel chemistry and evaluated to test their antagonism of the TR-coactivator interaction. Selected active compounds were evaluated in secondary confirmatory assays including regulation of thyroid response element driven transcription in reporter constructs and native genes. In addition the selected SNPT's shown to be selective for TR relative to other nuclear hormone receptor (NR).
PMCID: PMC3308170  PMID: 22324546
5.  Optimization of Propafenone Analogues as Anti-Malarial Leads 
Journal of medicinal chemistry  2011;54(21):7477-7485.
Propafenone, a class Ic antiarrythmic drug, inhibits growth of cultured Plasmodium falciparum. While the drug’s potency is significant, further development of propafenone as an antimalarial would require divorcing the antimalarial and cardiac activities as well as improving the pharmacokinetic profile of the drug. A small array of propafenone analogs was designed and synthesized to address the cardiac ion channel and PK liabilities. Testing of this array revealed potent inhibitors of the 3D7 (drug sensitive) and K1 (drug resistant) strains of P. falciparum that possessed significantly reduced ion channel effects and improved metabolic stability. Propafenone analogues are unusual among antimalarial leads in that they are more potent against the multi-drug resistant K1 strain of P. falciparum compared to the 3D7 strain.
PMCID: PMC3208124  PMID: 21955244
propafenone; malaria; microwave epoxide ring opening; hERG
6.  Targeting the p53 Pathway in Retinoblastoma with Subconjunctival Nutlin-3a 
Cancer research  2011;71(12):4205-4213.
Retinoblastoma is a rare childhood cancer of the retina that begins in utero and is diagnosed in the first years of life. The goals of retinoblastoma treatment are ocular salvage, vision preservation, and reduction of short-and long-term side effects without risking mortality due to tumor dissemination. To identify better chemotherapeutic combinations for the treatment of retinoblastoma, several groups have developed genetic mouse models and orthotopic xenograft models of human retinoblastoma for preclinical testing. Previous studies have implicated the MDMX protein in the suppression of the p53 pathway in retinoblastoma and shown that the MDM2/MDMX antagonist, nutlin-3a, can efficiently induce p53-mediated cell death in retinoblastoma cell lines. However, nutlin-3a cannot be administered systemically to treat retinoblastoma, because it has poor penetration across the blood-ocular barrier. Therefore, we developed an ocular formulation of nutlin-3a, nutlin-3aOC, and tested the pharmacokinetics and efficacy of this new formulation in genetic and human retinoblastoma orthotopic xenograft models of retinoblastoma. Here we show that nutlin-3aOC specifically and efficiently targets the p53 pathway and that the combination of nutlin-3aOC with systemic topotecan is a significantly better treatment for retinoblastoma than currently used chemotherapy in human orthotopic xenografts. Our studies provide a new standardized approach to evaluate and prioritize novel agents for incorporation into future clinical trials for retinoblastoma.
PMCID: PMC3116943  PMID: 21515735
7.  Evaluation of Diarylureas for Activity Against Plasmodium falciparum 
ACS Medicinal Chemistry Letters  2010;1(9):460-465.
A library of diarylurea insulin-like growth factor 1 receptor inhibitors was screened for activity against chloroquine-sensitive (3D7) and chloroquine-resistant (K1) strains of Plasmodium falciparum. The 4-aminoquinaldine-derived diarylureas displayed promising antimalarial potency. Further exploration of the B ring of 4-aminoquinaldinyl ureas allowed identification of several quinaldin-4-yl ureas 4{13, 39} and 4{13, 58} sufficiently potent against both 3D7 and K1 strains to qualify as bone fide leads.
PMCID: PMC3019604  PMID: 21243104
Malaria; diarylurea
8.  Evaluation of Diarylureas for Activity Against Plasmodium falciparum 
ACS medicinal chemistry letters  2010;1(9):460-465.
A library of diarylurea IGFR inhibitors was screened for activity against chloroquine-sensitive (3D7) and chloroquine-resistant (K1) strains of Plasmodium falciparum. The 4-aminoquinaldine-derived diarylureas displayed promising antimalarial potency. Further exploration of the B ring of 4-aminoquinaldinyl ureas allowed identification of several quinaldin-4-yl ureas 4{13, 39} and 4{13, 58} sufficiently potent against both 3D7 and K1 strains to qualify as bone fide leads.
PMCID: PMC3019604  PMID: 21243104
Malaria; diarylurea
9.  Synthesis and Structure-Activity Relationships of Antimalarial 4-oxo-3-carboxyl quinolones 
Bioorganic & medicinal chemistry  2010;18(7):2756-2766.
Malaria is endemic in tropical and subtropical regions of Africa, Asia, and the Americas. The increasing prevalence of multi-drug-resistant Plasmodium falciparum drives the ongoing need for the development of new antimalarial drugs. In this light, novel scaffolds to which the parasite has not been exposed are of particular interest. Recently, workers at the Swiss Tropical Institute discovered two novel 4-oxo-3-carboxyl quinolones active against the intra-erythrocytic stages of P. falciparum while carrying out rationally directed low-throughput screening of potential antimalarial agents as part of an effort directed by the World Health Organization. Here we report the design, synthesis, and preliminary pharmacologic characterization of a series of analogues of 4-oxo-3-carboxyl quinolones. These studies indicate that the series has good potential for preclinical development.
PMCID: PMC2850272  PMID: 20206533
10.  Determination of Nutlin-3a in Murine Plasma by Liquid Chromatography Electrospray Ionization Tandem Mass Spectrometry (LC-ESI-MS/MS) 
A sensitive and precise LC-ESI-MS/MS method for determination of nutlin-3a in murine plasma using ketoconazole as an internal standard was developed and validated. Plasma nutlin-3a samples were prepared by either a simple protein precipitation (PP) for the high concentration range (10 – 20,000 ng/mL) or by liquid-liquid extraction (LLE) for the low concentration range (0.25 – 300 ng/mL). Nutlin-3a and ketoconazole were separated on a modified C18 analytical column (4µ, 75x2 mm) with an isocratic mobile phase (acetonitrile/5mM HCOONH4 = 70/30, v/v). The retention times of nutlin-3a and ketoconazole were 1.14 and 1.45 minutes. Detection was achieved by a tandem MS system, monitoring m/z 582/99 and m/z 532/82 for nutlin-3a and ketoconazole, respectively. The PP method was linear in a range of 10 – 20,000 ng/mL (R2 ≥0.993) and the LLE method was linear in a range of 0.25 – 300 ng/mL (R2 ≥0.992). The mean recoveries for PP and LLE were 24% and 78%, respectively. Within-day and between-day precisions were ≤ 4.5% for PP and were ≤ 4.9% for LLE. Within-day and between-day accuracies (% error) ranged from 4.8 to −7.9 for PP, and from −0.2 to −8.4 for LLE. The two extraction methods produced equivalent results, allowing use of both within the same study. This method has been applied to the measurement of nutlin-3a concentrations in murine plasma samples obtained from a preclinical pharmacokinetic study.
PMCID: PMC2814893  PMID: 19931997
nutlin-3a; liquid-liquid extraction (LLE); protein precipitation (PP); liquid chromatography electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS)
11.  Podophyllotoxin Analogues Active versus Trypanosoma brucei 
In an effort to discover novel anti-trypanosomal compounds, a series of podophyllotoxin analogues coupled to non-steroidal anti-inflammatory drugs (NSAIDs) has been synthesized and evaluated for activity versus Trypanosoma brucei and a panel of human cell lines, revealing compounds with low nano-molar potencies. It was discovered that coupling of NSAIDs to podophyllotoxin increased the potencies of both compounds over 1300-fold. The compounds were shown to be cytostatic in nature and seem to act via depolymerization of tubulin in a manner consistent with the known activities of podophyllotoxin. The potencies against T. brucei correlated directly with LogP values of the compounds, suggesting that the conjugates are acting as hydrophobic tags allowing podophyllotoxin to enter the cell.
PMCID: PMC2826502  PMID: 20129783
12.  Chemical genetics of Plasmodium falciparum 
Nature  2010;465(7296):311-315.
Malaria caused by Plasmodium falciparum is a catastrophic disease worldwide (880,000 deaths yearly). Vaccine development has proved difficult and resistance has emerged for most antimalarials. In order to discover new antimalarial chemotypes, we have employed a phenotypic forward chemical genetic approach to assay 309,474 chemicals. Here we disclose structures and biological activity of the entire library, many of which exhibited potent in vitro activity against drug resistant strains, and detailed profiling of 172 representative candidates. A reverse chemical genetic study identified 19 new inhibitors of 4 validated drug targets and 15 novel binders among 61 malarial proteins. Phylochemogenetic profiling in multiple organisms revealed similarities between Toxoplasma gondii and mammalian cell lines and dissimilarities between P. falciparum and related protozoans. One exemplar compound displayed efficacy in a murine model. Overall, our findings provide the scientific community with new starting points for malaria drug discovery.
PMCID: PMC2874979  PMID: 20485428
13.  Structure-guided development of selective TbcatB inhibitors 
Journal of medicinal chemistry  2009;52(20):6489-6493.
The trypanosomal cathepsin TbcatB is essential for parasite survival and is an attractive therapeutic target. Herein we report the structure-guided development of TbcatB inhibitors with specificity relative to rhodesain and human cathepsins B and L. Inhibitors were tested for enzymatic activity, trypanocidal activity, and general cytotoxicity. These data chemically validate TbcatB as a drug target, and demonstrate that it is possible to potently and selectively inhibit TbcatB relative to trypanosomal and human homologues.
PMCID: PMC2762491  PMID: 19769357
14.  Novel Flufenamic Acid Analogs as Inhibitors of Androgen Receptor Mediated Transcription 
ACS chemical biology  2009;4(10):834-843.
The androgen receptor (AR), which mediates the signals of androgens, plays a crucial role in prostate related diseases. Although widely used, currently marketed anti-androgenic drugs have significant side effects. Several studies have revealed that non-steroidal anti-inflammatory drugs, like flufenamic acid, block AR transcriptional activity. Herein we describe the development of small molecule analogs of flufenamic acid that antagonize AR. This novel class of AR inhibitors binds to the hormone binding site, blocks AR transcription activity, and acts on AR target genes.
PMCID: PMC2763043  PMID: 19645433
Androgen receptor; transcription factor; anti-androgen; flufenamic acid
15.  Improvement of Pharmacological Properties of Irreversible Thyroid Receptor Coactivator Binding Inhibitors 
Journal of medicinal chemistry  2009;52(13):3892-3901.
We have previously reported the discovery and preliminary structure activity relationships of a series of β-aminoketones that disrupt the binding of coactivators to TR. However, the most active compounds had moderate inhibitory potency and relatively high cytotoxicity, resulting in narrow therapeutic index. Additionally, preliminary evaluation of in vivo toxicology revealed a significant dose related cardiotoxicity. Here we describe the improvement of pharmacological properties of thyroid hormone receptor coactivator binding inhibitors. A comprehensive survey of the effects of substitutents in key areas of the molecule was carried out, based on mechanistic insight from the earlier report. This study revealed that both electron withdrawing and hydrophobic substituents on the aromatic ring led to higher potency. On the other hand, moving from an alkyl to a sulfonyl alkyl side chain led to reduced cytotoxicity. Finally, utilization of amine moieties having low pKa’s resulted in lowered ion channel activity without any loss of pharmacological activity.
PMCID: PMC2753520  PMID: 19469546
16.  Discovery of trypanocidal thiosemicarbazone inhibitors of rhodesain and TbcatB 
Human African trypanosomiasis (HAT) is caused by the protozoan parasite Trypanosoma brucei. The cysteine proteases of T.brucei have been shown to be crucial for parasite replication and represent an attractive point for therapeutic intervention. Herein we describe the synthesis of a series of thiosemicarbazones and their activity against the trypanosomal cathepsins TbcatB and rhodesain, as well as human cathepsins L and B. The activity of these compounds was determined against cultured T.brucei, and specificity was assessed with a panel of four mammalian cell lines.
PMCID: PMC2435229  PMID: 18420405

Results 1-16 (16)