Tumor Cells Require Thymidylate Kinase to Prevent dUTP Incorporation during DNA Repair

The synthesis of dTDP is unique because there is a requirement for thymidylate kinase (TMPK). All other dNDPs including dUDP are directly produced by ribonucleotide reductase (RNR). We report the binding of TMPK and RNR at sites of DNA damage. In tumor cells, when TMPK function is blocked, dUTP is incorporated during DNA double-strand break (DSB) repair. Disrupting RNR recruitment to damage sites or reducing the expression of the R2 subunit of RNR prevents the impairment of DNA repair by TMPK intervention, indicating that RNR contributes to dUTP incorporation during DSB repair. We identified a cell-permeable nontoxic inhibitor of TMPK that sensitizes tumor cells to doxorubicin in vitro and in vivo, suggesting its potential as a therapeutic option. Cancer Cell 2012, 22, 36-50.
A Practical Synthesis of Zanamivir Phosphonate Congeners
with Potent Anti-influenza Activity

Two phosphonate compounds 4-amino-1-phosphono-DANA and phosphono-zanamivir are synthesized and shown more potent than zanamivir against the neuraminidases of avian and human influenza viruses, including the oseltamivir-resistant strains. For the first time, the practical synthesis of these phosphonate compounds is realized by conversion of sialic acid to peracetylated phosphono-DANA diethyl ester as a key intermediate in three steps by a novel approach. J. Am. Chem. Soc. 2011, 133, 17959-17965.
Intramolecular ion-pair
prodrugs of zanamivir and guanidino-oseltamivir

Zanamivir (ZA) is a potent
anti-influenza drug, but it cannot be administrated orally because
of the hydrophilic carboxylate and guanidinium groups. The ester
prodrugs ZA–HNAP was prepared to incorporate a
1-hydroxy-2-naphthoic (HNAP) moiety to attain good lipophilicity in
the intramolecular ion-pairing forms. ZA–HNAP resumed high
anti-influenza activity (EC50 = 48 nM), in cell-based
anti-influenza assays, by releasing zanamivir along with nontoxic
HNAP. Bioorg. Med. Chem.
2011, 19, 4796–4802.
A New
Drug Design Targeting the Adenosinergic System for Huntington’s
Disease: Novel Dual-Action Compounds Targeting Adenosine A2A
Receptor and Adenosine Transporter

A novel compound N6-(4-hydroxybenzyl)adenosine
isolated from Gastrodia elata, which has been shown to be a
potential therapeutic agent for preventing and treating
neurodegenerative disease, is found to target both the adenosine A2A
receptor (A2AR) and the equilibrative nucleoside
transporter 1 (ENT1). As A2AR and ENT1 are proximal in
the synaptic crevice of striatum, where the mutant huntingtin
aggregate is located, the dual-action compounds concomitantly
targeting these two membrane proteins may be beneficial for the
therapy of Huntington’s disease. To design the desired dual-action
compounds, the pharmacophore models of the A2AR agonists
and the ENT1 inhibitors are constructed. Accordingly, potentially
active compounds are designed and then synthesized, if the predicted
activity is within acceptable ranges, by chemical modification of
adenosine, particularly at the N6 and C5'
positions. Indeed, some of the designed compounds exhibit
significant dual-action property on both A2AR and ENT1.
In agreement with the competitive ligand binding assay, these
compounds also prevent apoptosis of serum-deprived PC12 cells,
rendering a crucial function in neuroprotection and potential
medical treatment of neurodegenerative diseases.
PLoS One 2011, 6,
e20934. ChemMedChem
2011, 6, 1390–1400.
Synergistic Effect
of Zanamivir–Porphyrin Conjugates on Inhibition of Neuraminidase and
Inactivation of Influenza Virus
New anti-influenza agents of
tetravalent zanamivir on porphyrin scaffold were synthesized. These
compounds are ten to hundred times more potent in inhibiting
influenza replications, even though they are somewhat less potent in
neuraminidase inhibition than the monomeric zanamivir. The enhanced
anti-influenza activity is probably attributable to the additional
viral inactivation by singlet oxygen due to sensitization of the
porphyrin moiety, which is brought in close proximity of virus by
the conjugated zanamivir in a manner resembling the “magic bullet”
mechanism.
J.
Med. Chem. 2009, 52, 4903–4910.
A Concise and Flexible Synthesis of
the Potent Anti-Influenza Agents Tamiflu and Tamiphosphor

We report safer and more
commercially viable synthetic methods for both anti-influenza drugs
Tamiflu and Tamiphosphor using bromobenzene as the starting
material. This is an innovative procedure in which the bromine atom
is converted to carboxyl or phosphonate groups at the later stage.
All reactions are handled without using potentially hazardous
intermediates or toxic reagents, and as most of the reactions
occurred in a regio- and stereoselective fashion to give crystalline
products throughout the synthesis, the isolation procedures were
relatively simple and cost effective.
Like Tamiflu, Tamiphosphor can be taken orally, and functions as an
inhibitor of the neuraminidase active site of the H5N1/H1N1 viruses.
However, Tamiphosphor proves to be more effective due to its higher
enzyme inhibition. Survival rates and recovery rates of infected
mice treated with Tamiphosphor both show better results.
Angew. Chem. Int. Ed. 2008, 47, 5788-5791.
Structure and Bioactivity of the Polysaccharides in Medicinal Plant
Dendrobium huoshanense

Detailed structures of the active
polysaccharides extracted from the leaf and stem cell walls and
mucilage of Dendrobium huoshanense are determined by using
various techniques, including chromatographic, spectroscopic,
chemical, and enzymatic methods. The mucilage polysaccharide
exhibits specific functions in activating murine splenocytes to
produce several cytokines including IFN-γ, IL-10, IL-6, and IL-1α,
as well as hematopoietic growth factors GM-CSF and G-CSF. However,
the deacetylated mucilage obtained from an alkaline treatment fails
to induce cytokine production. The structure and bioactivity of
mucilage components are validated by further fractionation. This is
the first study that provides clear evidence for the structure and
activity relationship of the polysaccharide in D. huoshanense
.
Bioorg. Med. Chem. 2008, 16, 6054-6068.
Synthesis of Tamiflu and
its Phosphonate Congeners Possessing Potent Anti-Influenza Activity

Using D-xylose as an appropriate
chiral precursor, we have synthesized active neuraminidase inhibitor
oseltamivir, antiflu drug Tamiflu, and novel phosphonate congeners
that exhibit even stronger antiflu activities by inhibiting the
neuraminidases of the wild-type and H274Y mutant of H1N1 and H5N1
viruses. Discovery of such potent neuraminidase inhibitors will
offer an opportunity to the development of new anti-influenza drugs.
J. Am. Chem. Soc. 2007, 129,
11892–11893.
Discovery of Potent Anilide Inhibitors against the Severe Acute
Respiratory Syndrome 3CL Protease

A diversified library of peptide
anilides was prepared, and their inhibition activities against the
SARS-CoV 3CL protease were examined by a fluorogenic
tetradecapeptide substrate. The most potent inhibitor is an anilide
derived from 2-chloro-4-nitroaniline, L-phenylalanine and 4-(dimethylamino)benzoic
acid. This anilide is a competitive inhibitor of the SARS-CoV 3CL
protease with Ki = 0.03 M. The molecular docking experiment
indicates that the P1 residue of this anilide inhibitor is distant
from the nucleophilic SH of Cys145 in the active site.
J. Med. Chem. 2005, 48, 4469–4473.
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