John A Secrist

Publications (48)130.75 Total impact

• Article: Synthesis and SAR of geminal substitutions at the C5' carbosugar position of pyrimidine-derived HCV inhibitors.

  Vishal A Verma, Randall Rossman, Frank Bennett, Lei Chen, Stephen Gavalas, Vinay Girijavallabhan, Yuhua Huang, Seong-Heon Kim, Aneta Kosinski, Patrick Pinto, [......], Joseph A Maddry, Subramaniam Ananthan, John A Secrist, Cheng Li, Robert Chase, Stephanie Curry, Hsueh-Cheng Huang, Xiao Tong, F George Njoroge, Ashok Arasappan
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  ABSTRACT: The installation of geminal substitution at the C5' position of the carbosugar in our pyrimidine-derived hepatitis C inhibitor series is reported. SAR studies around the C5' position led to the installation of the dimethyl group as the optimal functionality. An improved route was subsequently designed to access these substitutions. Expanded SAR at the C2 amino position led to the utilization of C2 ethers. These compounds exhibited good potency, high selectivity, and excellent plasma exposure and bioavailability in rodent as well as in higher species.
  Bioorganic & medicinal chemistry letters 09/2012; 22(22):6967-73. · 2.65 Impact Factor
• Article: Pyridofuran substituted pyrimidine derivatives as HCV replication (replicase) inhibitors.

  Frank Bennett, Hollis S Kezar, Vinay Girijavallabhan, Yuhua Huang, Regina Huelgas, Randall Rossman, Neng-Yang Shih, John J Piwinski, Malcolm MacCoss, Cecil D Kwong, [......], Joseph A Maddry, Subramaniam Ananthan, John A Secrist, Cheng Li, Robert Chase, Stephanie Curry, Hsueh-Cheng Huang, Xiao Tong, F George Njoroge, Ashok Arasappan
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  ABSTRACT: Introduction of nitrogen atom into the benzene ring of a previously identified HCV replication (replicase) benzofuran inhibitor 2, resulted in the discovery of the more potent pyridofuran analogue 5. Subsequent introduction of small alkyl and alkoxy ligands into the pyridine ring resulted in further improvements in replicon potency. Replacement of the 4-chloro moiety on the pyrimidine core with a methyl group, and concomitant monoalkylation of the C-2 amino moiety resulted in the identification of several inhibitors with desirable characteristics. Inhibitor 41, from the monosubstituted pyridofuran and inhibitor 50 from the disubstituted series displayed excellent potency, selectivity (GAPDH/MTS CC(50)) and PK parameters in all species studied, while the selectivity in the thymidine incorporation assay (DNA·CC(50)) was low.
  Bioorganic & medicinal chemistry letters 08/2012; 22(15):5144-9. · 2.65 Impact Factor
• Article: Preclinical combination therapy of thiarabine plus various clinical anticancer agents.

  William R Waud, Karen S Gilbert, John A Secrist
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  ABSTRACT: Thiarabine is undergoing clinical trials. In support of that effort combination therapy of thiarabine plus six clinical anticancer agents was evaluated using various human tumor xenograft models. The antitumor activity of thiarabine in combination appeared to be greater than additive with irinotecan (DLD-1 colon), paclitaxel (PC-3 prostate), cisplatin (PC-3 prostate), or cyclophosphamide (RL lymphoma), additive with irinotecan (NCI-H460 NSCLC), cisplatin (NCI-H460 NSCLC) or methotrexate (CCRF-CEM leukemia), and less than additive with irinotecan (HT29 colon), paclitaxel (NCI-H460 NSCLC) or cisplatin (NCI-H23 NSCLC). Combining thiarabine with irinotecan, paclitaxel, cisplatin, or cyclophosphamide should receive consideration in the clinical treatment of cancer.
  Nucleosides Nucleotides &amp Nucleic Acids 08/2012; 31(8):630-46. · 0.90 Impact Factor
• Article: Synthesis and SAR of pyridothiazole substituted pyrimidine derived HCV replication inhibitors.

  Vinay M Girijavallabhan, Carmen Alvarez, Frank Bennett, Lei Chen, Stephen Gavalas, Yuhua Huang, Seong-Heon Kim, Aneta Kosinski, Patrick Pinto, Razia Rizvi, [......], Joseph A Maddry, Subramaniam Ananthan, John A Secrist, Cheng Li, Robert Chase, Stephanie Curry, Hsueh-Cheng Huang, Xiao Tong, F George Njoroge, Ashok Arasappan
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  ABSTRACT: Introduction of a nitrogen atom into the benzene ring of a previously identified HCV replication (replicase) benzothiazole inhibitor 1, resulted in the discovery of the more potent pyridothiazole analogues 3. The potency and PK properties of the compounds were attenuated by the introductions of various functionalities at the R(1), R(2) or R(3) positions of the molecule (compound 3). Inhibitors 38 and 44 displayed excellent potency, selectivity (GAPDH/MTS CC(50)), PK parameters in all species studied, and cross genotype activity.
  Bioorganic & medicinal chemistry letters 07/2012; 22(17):5652-7. · 2.65 Impact Factor
• Article: 5-Benzothiazole substituted pyrimidine derivatives as HCV replication (replicase) inhibitors.

  Ashok Arasappan, Frank Bennett, Vinay Girijavallabhan, Yuhua Huang, Regina Huelgas, Carmen Alvarez, Lei Chen, Stephen Gavalas, Seong-Heon Kim, Aneta Kosinski, [......], Robert C Reynolds, Joseph A Maddry, Subramaniam Ananthan, John A Secrist, Cheng Li, Robert Chase, Stephanie Curry, Hsueh-Cheng Huang, Xiao Tong, F George Njoroge
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  ABSTRACT: Based on a previously identified HCV replication (replicase) inhibitor 1, SAR efforts were conducted around the pyrimidine core to improve the potency and pharmacokinetic profile of the inhibitors. A benzothiazole moiety was found to be the optimal substituent at the pyrimidine 5-position. Due to potential reactivity concern, the 4-chloro residue was replaced by a methyl group with some loss in potency and enhanced rat in vivo profile. Extensive investigations at the C-2 position resulted in identification of compound 16 that demonstrated very good replicon potency, selectivity and rodent plasma/target organ concentration. Inhibitor 16 also demonstrated good plasma levels and oral bioavailability in dogs, while monkey exposure was rather low. Chemistry optimization towards a practical route to install the benzothiazole moiety resulted in an efficient direct C-H arylation protocol.
  Bioorganic & medicinal chemistry letters 03/2012; 22(9):3229-34. · 2.65 Impact Factor
• Article: Isolation and characterization of a murine P388 leukemia line resistant to thiarabine.

  William R Waud, William B Parker, Karen S Gilbert, John A Secrist
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  ABSTRACT: A murine P388 leukemia line fully resistant to thiarabine was obtained after five courses of intraperitoneal treatment (daily for nine consecutive days). The subline was sensitive as was the parental P388/0 line to 5-fluorouracil, gemcitabine, cyclophosphamide, cisplatin, melphalan, BCNU, mitomycin C, doxorubicin, mitoxantrone, etoposide, irinotecan, vincristine, and paclitaxel, but was cross resistant (at least marginally) to three antimetabolites: palmO-ara-C, fludarabine phosphate, and methotrexate. The deoxycytidine kinase activity in the subline was comparable to that for P388/0, whereas the dCMP deaminase activity was 43% of that for P388/0. No deoxycytidine deaminase activity was detected in either of the leukemias. There appeared to be little, if any, difference in the metabolism of deoxycytidine, cytidine, or thiarabine in the two leukemias.
  Nucleosides Nucleotides &amp Nucleic Acids 01/2012; 31(1):14-27. · 0.90 Impact Factor
• Article: Novel substituted pyrimidines as HCV replication (replicase) inhibitors.

  Cecil D Kwong, Jeremy L Clark, Anita T Fowler, Feng Geng, Hollis S Kezar, Abhijit Roychowdhury, Robert C Reynolds, Joseph A Maddry, Subramaniam Ananthan, John A Secrist, Neng-Yang Shih, John J Piwinski, Cheng Li, Boris Feld, Hsueh-Cheng Huang, Xiao Tong, F George Njoroge, Ashok Arasappan
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  ABSTRACT: Compound 1 was identified as a HCV replication inhibitor from screening/early SAR triage. Potency improvement was achieved via modulation of substituent on the 5-azo linkage. Due to potential toxicological concern, the 5-azo linkage was replaced with 5-alkenyl or 5-alkynyl moiety. Analogs containing the 5-alkynyl linkage were found to be potent inhibitors of HCV replication. Further evaluation identified compounds 53 and 63 with good overall profile, in terms of replicon potency, selectivity and in vivo characteristics. Initial target engagement studies suggest that these novel carbanucleoside-like derivatives may inhibit the HCV replication complex (replicase).
  Bioorganic & medicinal chemistry letters 12/2011; 22(2):1160-4. · 2.65 Impact Factor
• Article: Synthesis and evaluation of the substrate activity of C-6 substituted purine ribosides with E. coli purine nucleoside phosphorylase: palladium mediated cross-coupling of organozinc halides with 6-chloropurine nucleosides.

  Abdalla E A Hassan, Reham A I Abou-Elkhair, James M Riordan, Paula W Allan, William B Parker, Rashmi Khare, William R Waud, John A Montgomery, John A Secrist
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  ABSTRACT: A series of C-6 alkyl, cycloalkyl, and aryl-9-(β-d-ribofuranosyl)purines were synthesized and their substrate activities with Escherichia coli purine nucleoside phosphorylase (E. coli PNP) were evaluated. (Ph(3)P)(4)Pd-mediated cross-coupling reactions of 6-chloro-9-(2,3,5-tri-O-acetyl-β-d-ribofuranosyl)-purine (6) with primary alkyl (Me, Et, n-Pr, n-Bu, isoBu) zinc halides followed by treatment with NH(3)/MeOH gave the corresponding 6-alkyl-9-(β-d-ribofuranosyl)purine derivatives 7-11, respectively, in good yields. Reactions of 6 with cycloalkyl(propyl, butyl, pentyl)zinc halides and aryl (phenyl, 2-thienyl)zinc halides gave under similar conditions the corresponding 6-cyclopropyl, cyclobutyl, cyclopentyl, phenyl, and thienyl -9-(β-d-ribofuranosyl)purine derivatives 12-16, respectively in high yields. E. coli PNP showed a high tolerance to the steric and hydrophobic environment at the 6-position of the synthesized purine ribonucleosides. Significant cytotoxic activity was observed for 8, 12, 15, and 16. Evaluation of 12 and 16 against human tumor xenografts in mice did not demonstrate any selective antitumor activity. In addition, 6-methyl-9-(β-d-arabinofuranosyl)purine (18) was prepared and evaluated.
  European journal of medicinal chemistry 11/2011; 47(1):167-74. · 3.27 Impact Factor
• Article: Isolation and characterization of a murine P388 leukemia line resistant to clofarabine.

  William R Waud, Karen S Gilbert, William B Parker, John A Secrist
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  ABSTRACT: A murine P388 leukemia line fully resistant to clofarabine was obtained after only two courses of intraperitoneal treatment (three times a day for nine consecutive days). The resistance was stable for at least 13 weeks without treatment. The subline was as sensitive to 5-fluorouracil, methotrexate, cyclophosphamide, cisplatin, melphalan, BCNU, doxorubicin, etoposide, irinotecan, vincristine, and docetaxel as was the parental P388/0 line but was cross-resistant to five antimetabolites [palmO-ara-C, 4'-thio-ara-C, fludarabine phosphate, cladribine, and gemcitabine-all of which require deoxycytidine kinase for activation] and paclitaxel. The subline had less than 1% of the deoxycytidine kinase activity in comparison to P388/0.
  Nucleosides Nucleotides &amp Nucleic Acids 11/2011; 30(11):826-38. · 0.90 Impact Factor
• Article: Binding and inhibition of human spermidine synthase by decarboxylated S-adenosylhomocysteine.

  Jolita Sečkutė, Diane E McCloskey, H Jeanette Thomas, John A Secrist, Anthony E Pegg, Steven E Ealick
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  ABSTRACT: Aminopropyltransferases are essential enzymes that form polyamines in eukaryotic and most prokaryotic cells. Spermidine synthase (SpdS) is one of the most well-studied enzymes in this biosynthetic pathway. The enzyme uses decarboxylated S-adenosylmethionine and a short-chain polyamine (putrescine) to make a medium-chain polyamine (spermidine) and 5'-deoxy-5'-methylthioadenosine as a byproduct. Here, we report a new spermidine synthase inhibitor, decarboxylated S-adenosylhomocysteine (dcSAH). The inhibitor was synthesized, and dose-dependent inhibition of human, Thermatoga maritima, and Plasmodium falciparum spermidine synthases, as well as functionally homologous human spermine synthase, was determined. The human SpdS/dcSAH complex structure was determined by X-ray crystallography at 2.0 Å resolution and showed consistent active site positioning and coordination with previously known structures. Isothermal calorimetry binding assays confirmed inhibitor binding to human SpdS with K(d) of 1.1 ± 0.3 μM in the absence of putrescine and 3.2 ± 0.1 μM in the presence of putrescine. These results indicate a potential for further inhibitor development based on the dcSAH scaffold.
  Protein Science 08/2011; 20(11):1836-44. · 2.80 Impact Factor
• Article: High throughput screening of a library based on kinase inhibitor scaffolds against Mycobacterium tuberculosis H37Rv.

  Robert C Reynolds, Subramaniam Ananthan, Ellen Faaleolea, Judith V Hobrath, Cecil D Kwong, Clinton Maddox, Lynn Rasmussen, Melinda I Sosa, Elizabeth Thammasuvimol, E Lucile White, Wei Zhang, John A Secrist
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  ABSTRACT: Kinase targets are being pursued in a variety of diseases beyond cancer, including immune and metabolic as well as viral, parasitic, fungal and bacterial. In particular, there is a relatively recent interest in kinase and ATP-binding targets in Mycobacterium tuberculosis in order to identify inhibitors and potential drugs for essential proteins that are not targeted by current drug regimens. Herein, we report the high throughput screening results for a targeted library of approximately 26,000 compounds that was designed based on current kinase inhibitor scaffolds and known kinase binding sites. The phenotypic data presented herein may form the basis for selecting scaffolds/compounds for further enzymatic screens against specific kinase or other ATP-binding targets in Mycobacterium tuberculosis based on the apparent activity against the whole bacteria in vitro.
  Tuberculosis (Edinburgh, Scotland) 06/2011; 92(1):72-83. · 2.54 Impact Factor
• Article: The Alabama Drug Discovery Alliance: a collaborative partnership to facilitate academic drug discovery.

  Maaike Everts, W Blaine Knight, David R Harris, John A Secrist, Richard J Whitley
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  ABSTRACT: The Alabama Drug Discovery Alliance is a collaboration between the University of Alabama at Birmingham and Southern Research Institute that aims to support the discovery and development of therapeutic molecules that address an unmet medical need. The alliance builds on the expertise present at both institutions and has the dedicated commitment of their respective technology transfer and intellectual property offices to guide any commercial opportunities that may arise from the supported efforts. Although most projects involve high throughput screening, projects at any stage in the drug discovery and development pathway are eligible for support. Irrespective of the target and stage of any project, well-functioning interdisciplinary teams are crucial to a project's progress. These teams consist of investigators with a wide variety of expertise from both institutions to contribute to the program's success.
  Pharmaceutical Research 03/2011; 28(7):1454-9. · 4.09 Impact Factor
• Article: Lack of in vivo cross-resistance with 4'-thio-ara-C against drug-resistant murine P388 and L1210 leukemias.

  William R Waud, Karen S Gilbert, John A Secrist
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  ABSTRACT: 4'-Thio-β-D-arabinofuranosylcytosine (4'-thio-ara-C), which has shown a broad spectrum of antitumor activity against human tumor systems in mice and is undergoing clinical trials, was evaluated for cross-resistance to seven clinical agents in order to identify potentially useful guides for patient selection for further clinical trials of 4'-thio-ara-C and possible noncross-resistant drug combinations with 4'-thio-ara-C. A drug resistance profile for 4'-thio-ara-C, which was administered intraperitoneally daily for nine consecutive days, was obtained using seven drug-resistant P388 and L1210 leukemias that were implanted intraperitoneally in mice. Multidrug-resistant P388 leukemias (leukemias resistant to doxorubicin, etoposide, or paclitaxel) exhibited no cross-resistance to 4'-thio-ara-C. Leukemias resistant to camptothecin, cisplatin, and 5-fluorouracil were also not cross-resistant to 4'-thio-ara-C. Only the leukemia resistant to 1-β-D-arabinofuranosylcytosine was cross-resistant to 4'-thio-ara-C. The data suggest that (1) it may be important to exclude or to monitor with extra care patients who have previously been treated with 1-β-D-arabinofuranosylcytosine and (2) the lack of cross-resistance seen with 4'-thio-ara-C may contribute to therapeutic synergism when 4'-thio-ara-C is combined with other agents.
  Cancer Chemotherapy and Pharmacology 11/2010; 68(2):399-403. · 2.83 Impact Factor
• Article: Alteration of the carbohydrate for deoxyguanosine analogs markedly changes DNA replication fidelity, cell cycle progression and cytotoxicity.

  Jessica J O'Konek, Brendon Ladd, Sheryl A Flanagan, Mike M Im, Paul D Boucher, Tico S Thepsourinthone, John A Secrist, Donna S Shewach
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  ABSTRACT: Nucleoside analogs are efficacious cancer chemotherapeutics due to their incorporation into tumor cell DNA. However, they exhibit vastly different antitumor efficacies, suggesting that incorporation produces divergent effects on DNA replication. Here we have evaluated the consequences of incorporation on DNA replication and its fidelity for three structurally related deoxyguanosine analogs: ganciclovir (GCV), currently in clinical trials in a suicide gene therapy approach for cancer, D-carbocyclic 2'-deoxyguanosine (CdG) and penciclovir (PCV). GCV and CdG elicited similar cytotoxicity at low concentrations, whereas PCV was 10-100-fold less cytotoxic in human tumor cells. DNA replication fidelity was evaluated using a supF plasmid-based mutation assay. Only GCV induced a dose-dependent increase in mutation frequency, predominantly GC-->TA transversions, which contributed to cytotoxicity and implicated the ether oxygen in mutagenicity. Activation of mismatch repair with hydroxyurea decreased mutations but failed to repair the GC-->TA transversions. GCV slowed S-phase progression and CdG also induced a G2/M block, but both drugs allowed completion of one cell cycle after drug treatment followed by cell death in the second cell cycle. In contrast, PCV induced a lengthy early S-phase block due to profound suppression of DNA synthesis, with cell death in the first cell cycle after drug treatment. These data suggest that GCV and CdG elicit superior cytotoxicity due to their effects in template DNA, whereas strong inhibition of nascent strand synthesis by PCV may protect against cytotoxicity. Nucleoside analogs based on the carbohydrate structures of GCV and CdG is a promising area for antitumor drug development.
  Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 12/2009; 684(1-2):1-10. · 2.85 Impact Factor
• Article: Inhibition of herpesvirus replication by 5-substituted 4'-thiopyrimidine nucleosides.

  Mark N Prichard, Debra C Quenelle, Caroll B Hartline, Emma A Harden, Geraldine Jefferson, Samuel L Frederick, Shannon L Daily, Richard J Whitley, Kamal N Tiwari, Joseph A Maddry, John A Secrist, Earl R Kern
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  ABSTRACT: A series of 4'-thionucleosides were synthesized and evaluated for activities against orthopoxviruses and herpesviruses. We reported previously that one analog, 5-iodo-4'-thio-2'-deoxyuridine (4'-thioIDU), exhibits good activity both in vitro and in vivo against two orthopoxviruses. This compound also has good activity in cell culture against many of the herpesviruses. It inhibited the replication of herpes simplex virus type 1 (HSV-1), HSV-2, and varicella-zoster virus with 50% effective concentrations (EC(50)s) of 0.1, 0.5, and 2 microM, respectively. It also inhibited the replication of human cytomegalovirus (HCMV) with an EC(50) of 5.9 microM but did not selectively inhibit Epstein-Barr virus, human herpesvirus 6, or human herpesvirus 8. While acyclovir-resistant strains of HSV-1 and HSV-2 were comparatively resistant to 4'-thioIDU, it retained modest activity (EC(50)s of 4 to 12 microM) against these strains. Some ganciclovir-resistant strains of HCMV also exhibited reduced susceptibilities to the compound, which appeared to be related to the specific mutations in the DNA polymerase, consistent with the observed incorporation of the compound into viral DNA. The activity of 4'-thioIDU was also evaluated using mice infected intranasally with the MS strain of HSV-2. Although there was no decrease in final mortality rates, the mean length of survival after inoculation increased significantly (P < 0.05) for all animals receiving 4'-thioIDU. The findings from the studies presented here suggest that 4'-thioIDU is a good inhibitor of some herpesviruses, as well as orthopoxviruses, and this class of compounds warrants further study as a therapy for infections with these viruses.
  Antimicrobial Agents and Chemotherapy 09/2009; 53(12):5251-8. · 4.84 Impact Factor
• Article: High-throughput screening for inhibitors of Mycobacterium tuberculosis H37Rv.

  Subramaniam Ananthan, Ellen R Faaleolea, Robert C Goldman, Judith V Hobrath, Cecil D Kwong, Barbara E Laughon, Joseph A Maddry, Alka Mehta, Lynn Rasmussen, Robert C Reynolds, John A Secrist, Nice Shindo, Dustin N Showe, Melinda I Sosa, William J Suling, E Lucile White
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  ABSTRACT: There is an urgent need for the discovery and development of new antitubercular agents that target new biochemical pathways and treat drug resistant forms of the disease. One approach to addressing this need is through high-throughput screening of medicinally relevant libraries against the whole bacterium in order to discover a variety of new, active scaffolds that will stimulate new biological research and drug discovery. Through the Tuberculosis Antimicrobial Acquisition and Coordinating Facility (www.taacf.org), a large, medicinally relevant chemical library was screened against M. tuberculosis strain H37Rv. The screening methods and a medicinal chemistry analysis of the results are reported herein.
  Tuberculosis (Edinburgh, Scotland) 09/2009; 89(5):334-53. · 2.54 Impact Factor
• Article: Antituberculosis activity of the molecular libraries screening center network library.

  Joseph A Maddry, Subramaniam Ananthan, Robert C Goldman, Judith V Hobrath, Cecil D Kwong, Clinton Maddox, Lynn Rasmussen, Robert C Reynolds, John A Secrist, Melinda I Sosa, E Lucile White, Wei Zhang
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  ABSTRACT: There is an urgent need for the discovery and development of new antitubercular agents that target novel biochemical pathways and treat drug-resistant forms of the disease. One approach to addressing this need is through high-throughput screening of drug-like small molecule libraries against the whole bacterium in order to identify a variety of new, active scaffolds that will stimulate additional biological research and drug discovery. Through the Molecular Libraries Screening Center Network, the NIAID Tuberculosis Antimicrobial Acquisition and Coordinating Facility tested a 215,110-compound library against Mycobacterium tuberculosis strain H37Rv. A medicinal chemistry survey of the results from the screening campaign is reported herein.
  Tuberculosis (Edinburgh, Scotland) 09/2009; 89(5):354-63. · 2.54 Impact Factor
• Article: Regioselective metalation of 6-methylpurines: synthesis of fluoromethyl purines and related nucleosides for suicide gene therapy of cancer.

  Abdalla E A Hassan, William B Parker, Paula W Allan, John A Secrist
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  ABSTRACT: Metalation of 6-methyl-9-(tetrahydro-2H-pyran-2-yl)purine (10) with lithiating agents of varying basicities such as n-BuLi and LiHMDS in THF at -78 degrees C resulted in metalation at both of the 6-CH(3) moiety and the 8-CH position, irrespective of the molar equivalence of the base. On the other hand, a regioselective metalation at the 6-CH(3) moiety of 10 was observed with NaHMDS or KHMDS, under similar conditions. Treatment of the potassium salts of 10 and of the protected riboside derivative 6-methyl-9-(beta-D-2,3,5-tri-O-tert-butyldimethylsilylribofuranosyl)purine (22) with N-fluorobenzenesulfonamide (NFSI) at -78 degrees C gave the corresponding 6-fluoromethylpurine derivatives 11 and 23, respectively, in good yields. Deprotection of 11 and 23 under standard conditions gave 6-fluoromethylpurine (6-FMeP, 3) and 6-fluoromethyl-9-(beta-D-ribofuranosyl)purine (6-FMePR, 4), respectively, in high yield. Both 3 and 4 demonstrated cytotoxic activity against CCRF-CEM cells in culture. 6-FMePR is a good substrate for E. coli purine nucleoside phosphorylase (E. coli PNP) with a comparable substrate activity to that of the parent nucleoside, 6-methyl-9-(beta-D-ribofuranosyl)purine (6-MePR, 21). The cytotoxic activity of 6-FMeP along with the substrate activity of 6-FMePR with E. coli PNP meet the fundamental requirements for using 6-FMeP as a potential toxin in PNP/prodrug based cancer gene therapy.
  Nucleosides Nucleotides &amp Nucleic Acids 05/2009; 28(5):642-56. · 0.90 Impact Factor
• Article: Synthesis and anticancer evaluation of 4'-C-methyl-2'-fluoro arabino nucleosides.

  Kamal N Tiwari, Anita T Shortnacy-Fowler, William B Parker, William R Waud, John A Secrist
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  ABSTRACT: As part of an ongoing program to develop novel antitumor agents over the years, we have synthesized and evaluated a number of 4'-C-substituted nucleosides. A few years ago, we reported the first synthesis of 4'-C-hydroxymethyl-2'-fluoro arabino nucleosides, which did not exhibit any cytotoxicity. In our exploration of related compounds, we synthesized and evaluated the 4'-C-methyl-2'-fluoro arabino nucleosides in both the purine and pyrimidine series. In the pyrimidine series, 1-(4-C-methyl-2-fluoro-beta-D-arabinofuranosyl) cytosine (13) was found to be highly cytotoxic and had significant antitumor activity in mice implanted with human tumor xenografts. The synthesis and anticancer activity of this series of nucleosides are reported.
  Nucleosides Nucleotides &amp Nucleic Acids 05/2009; 28(5):657-77. · 0.90 Impact Factor
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  Available from: Wayne Guida

  Article: New insights into the design of inhibitors of human S-adenosylmethionine decarboxylase: studies of adenine C8 substitution in structural analogues of S-adenosylmethionine.

  Diane E McCloskey, Shridhar Bale, John A Secrist, Anita Tiwari, Thomas H Moss, Jacob Valiyaveettil, Wesley H Brooks, Wayne C Guida, Anthony E Pegg, Steven E Ealick
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  ABSTRACT: S-adenosylmethionine decarboxylase (AdoMetDC) is a critical enzyme in the polyamine biosynthetic pathway and depends on a pyruvoyl group for the decarboxylation process. The crystal structures of the enzyme with various inhibitors at the active site have shown that the adenine base of the ligands adopts an unusual syn conformation when bound to the enzyme. To determine whether compounds that favor the syn conformation in solution would be more potent AdoMetDC inhibitors, several series of AdoMet substrate analogues with a variety of substituents at the 8-position of adenine were synthesized and analyzed for their ability to inhibit hAdoMetDC. The biochemical analysis indicated that an 8-methyl substituent resulted in more potent inhibitors, yet most other 8-substitutions provided no benefit over the parent compound. To understand these results, we used computational modeling and X-ray crystallography to study C(8)-substituted adenine analogues bound in the active site.
  Journal of Medicinal Chemistry 03/2009; 52(5):1388-407. · 4.80 Impact Factor