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1.  Influence of the Length and Positioning of the Antiestrogenic Side Chain of Endoxifen and 4-Hydroxytamoxifen on Gene Activation and Growth of Estrogen Receptor Positive Cancer Cells 
Journal of Medicinal Chemistry  2014;57(11):4569-4583.
Tamoxifen has biologically active metabolites: 4-hydroxytamoxifen (4OHT) and endoxifen. The E-isomers are not stable in solution as Z-isomerization occurs. We have synthesized fixed ring (FR) analogues of 4OHT and endoxifen as well as FR E and Z isomers with methoxy and ethoxy side chains. Pharmacologic properties were documented in the MCF-7 cell line, and prolactin synthesis was assessed in GH3 rat pituitary tumor cells. The FR Z-isomers of 4OHT and endoxifen were equivalent to 4OHT and endoxifen. Other test compounds used possessed partial estrogenic activity. The E-isomers of FR 4OHT and endoxifen had no estrogenic activity at therapeutic serum concentrations. None of the newly synthesized compounds were able to down-regulate ER levels. Molecular modeling demonstrated that some compounds would each create a best fit with a novel agonist conformation of the ER. The results demonstrate modulation by the ER complex of cell replication or gene transcription in cancer.
PMCID: PMC4059272  PMID: 24805199
2.  The Effect of 5-Aminolevulinic Acid and its Derivatives on Protoporphyrin IX Accumulation and Apoptotic Cell Death in Castrate-Resistant Prostate Cancer Cells 
Urology  2012;80(6):1391.e1-1391.e7.
To examine whether pharmacologically relevant zinc-binding agents are capable of depleting XIAP in tumor cells. Our prior work reveals that treatment with zinc chelating agents induces selective down-regulation of the X-linked inhibitor of apoptosis protein (XIAP) in cancer cells of various origins. A precursor of the heme synthetic pathway, 5-aminolevulinic acid (5-ALA), is metabolized to protoporphyrin IX (PPIX), which is highly reactive with zinc. We assessed whether modified versions of 5-ALA with lipophilic side chains can enhance efficacy and selectivity with respect to PPIX accumulation, XIAP depletion, and TNF-related apoptosis-inducing ligand (TRAIL) – mediated apoptosis in human castration resistant prostate cancer (CRPC) cells.
Seven modified versions of 5-ALA (five esters and two amides) were synthesized. Levels of endogenous PPIX were examined by flow cytometry. XIAP expression was examined by Western blotting. TUNEL assay was used to assess cell apoptosis. Results were compared qualitatively.
Accumulation of endogenous PPIX by CRPC cells was shown to be directly related to the carbon chain length of the esterified 5-ALA derivatives. In fact, treatment with ALA-HE was superior to that achieved by 5-ALA with respect to XIAP down-regulation. 5-ALA and ALA-HE in combination with TRAIL significantly enhanced apoptotic cell death in CRPC cell lines.
Esterified derivatives of 5-ALA alone or in combination with other agents may provide therapeutic opportunities in treatment of CRPC by harnessing apoptotic pathways that are triggered by cellular zinc imbalance.
PMCID: PMC3514607  PMID: 22950992
Prostate cancer; 5-Aminolevulinic acid; Protoporphyrin IX; XIAP; Apoptosis
3.  Chemical Genetic Screening for Compounds that Preferentially Inhibit Growth of Methylthioadenosine Phosphorylase (MTAP) Deficient Saccharomyces Cerevisiae 
Methylthioadenosine phosphorylase (MTAP), a key enzyme in the methionine salvage pathway, is inactivated in a variety of human cancers. Since all human tissues express MTAP, it would be of potential interest to identify compounds that selectively inhibit the growth of MTAP deficient cells. To determine if MTAP inactivation could be targeted, we have performed a differential chemical genetic screen in isogenic MTAP+ and MTAP− S. cerevisiae. A low molecular weight compound library containing 30,080 unique compounds was screened for those that selectively inhibit growth of MTAP− yeast using a differential growth assay. One compound, containing a 1,3,4-thiadiazine ring, repeatedly showed a differential dose response, with MTAP− cells exhibiting a four-fold shift in IC50 compared to MTAP+ cells. Several structurally related derivatives of this compound also showed enhanced growth inhibition in MTAP− yeast. These compounds were also examined for growth inhibition of isogenic MTAP+ and MTAP− HT1080 fibrosarcoma cells, and four of the five compounds exhibited evidence of modest, but significant, increased potency in MTAP− cells. In summary, these studies show the feasibility of differential growth screening technology and have identified a novel class of compounds that can preferentially inhibit growth of MTAP− cells.
PMCID: PMC3019245  PMID: 21131597
Methionine Salvage Pathway; Drug screening; Yeast; Genetic-chemical interaction

Results 1-3 (3)