Papers by alan kozikowski
Bioorganic & Medicinal Chemistry Letters, 2014
Journal of Medicinal Chemistry, 2010
Our triazole-based histone deacetylase inhibitor (HDACI), octanedioic acid hydroxyamide [3-(1phen... more Our triazole-based histone deacetylase inhibitor (HDACI), octanedioic acid hydroxyamide [3-(1phenyl-1H-[1,2,3]triazol-4-yl)phenyl]amide (4a), suppresses pancreatic cancer cell growth in vitro, with the lowest IC 50 value of 20 nM against MiaPaca-2 cell. In this study, we continued our efforts to develop triazol-4-ylphenyl bearing hydroxamate analogs by embellishing the terminal phenyl ring of 4a with different substituents. The isoform inhibitory profile of these hydroxamate analogs was similar to those of 4a. All of these triazol-4-ylphenyl bearing hydroxamates are pan-HDACIs like SAHA. Moreover, compounds 4h and 11a were found to be very effective inhibitors of cancer cell growth in the HupT3 (IC 50 = 50 nM) and MiaPaca-2 (IC 50 = 40 nM) cancer cell lines, respectively. Compound 4a was found to re-activate the expression of CDK inhibitor proteins and to suppress pancreatic cancer cell growth in vivo. Taken together these data further support the value of the triazol-4-ylphenyl bearing hydroxamates in identifying potential pancreatic cancer therapies.
ChemInform, 1995
Chemical Modification of Ring C of Himbacine: Discovery of a Pharmacophoric Element for M2-Select... more Chemical Modification of Ring C of Himbacine: Discovery of a Pharmacophoric Element for M2-Selectivity. -The C-ring modified analogues (I) and (II) show less binding affinity and M2-selectivity than himbacine (III) itself. -(MALASKA, M. J.; FAUQ, A. H.; KOZIKOWSKI, A. P.; AAGAARD, P. J.; MCKINNEY, M.; Bioorg. Med.
Journal of Medicinal Chemistry, 2009
2-[2-Benzoylamino)benzoylamino]benzoic acid (1) was previously identified as a potent and nontoxi... more 2-[2-Benzoylamino)benzoylamino]benzoic acid (1) was previously identified as a potent and nontoxic antiadenoviral compound (Antimicrob. Agents Chemother. 2010, 54, 3871). Here, the potency of 1 was improved over three generations of compounds. We found that the ortho, ortho substituent pattern and the presence of the carboxylic acid of 1 are favorable for this class of compounds and that the direction of the amide bonds (as in 1) is obligatory. Some variability in the N-terminal moiety was tolerated, but benzamides appear to be preferred. The substituents on the middle and C-terminal rings were varied, resulting in two potent inhibitors, 35g and 35j, with EC(50) = 0.6 μM and low cell toxicity.
ChemInform, 1996
Synthesis of the 6-and 7-Hydroxylated Cocaines and Pseudococaines.
Journal of the Chemical Society, Chemical Communications, 1988
Journal of the Chemical Society, Perkin Transactions 1, 1996
... pyrimidone and pyrazole analogues, and their anticholinesterase activity Alan P. Kozikowski,&... more ... pyrimidone and pyrazole analogues, and their anticholinesterase activity Alan P. Kozikowski,"," Giuseppe Campiani? Vito Nacci: Alessandro Sega,' Ashima Saxena and Bhupendra P. Doctor' Georgetown University Medical ...
Molecular immunology, 2014
The anti-inflammatory cytokine IL-10 is a key modulator of immune responses. A better understandi... more The anti-inflammatory cytokine IL-10 is a key modulator of immune responses. A better understanding of the regulation of this cytokine offers the possibility of tipping the balance of the immune response toward either tolerance, or enhanced immune responses. Histone deacetylases (HDACs) have been widely described as negative regulators of transcriptional regulation, and in this context, the primarily nuclear protein HDAC11 was shown to repress il-10 gene transcriptional activity in antigen-presenting cells (APCs). Here we report that another HDAC, HDAC6, primarily a cytoplasmic protein, associates with HDAC11 and modulates the expression of IL-10 as a transcriptional activator. To our knowledge, this is the first demonstration of two different HDACs being recruited to the same gene promoter to dictate divergent transcriptional responses. This dynamic interaction results in dynamic changes in the expression of IL-10 and might help to explain the intrinsic plasticity of the APC to det...
AbstractÐA convenient synthesis of nonsymmetrical bivalent inhibitors of the serotonin transporte... more AbstractÐA convenient synthesis of nonsymmetrical bivalent inhibitors of the serotonin transporter is described. The synthesis utilizes polymer-supported reagents that allow for rapid access to novel bivalent ligands without the need for isolation or puri®cation of synthetic intermediates. #
AbstractÐ(AE)-10,10-Dimethylhuperzine A (2, DMHA) has been synthesized, and its enantiomers have ... more AbstractÐ(AE)-10,10-Dimethylhuperzine A (2, DMHA) has been synthesized, and its enantiomers have been separated using chiral HPLC. (À)-DMHA inhibits AChE with a K i value approaching that of (À)-huperzine A, whereas (+)-DMHA shows no AChE inhibitory activity. On the other hand, both enantiomers are equally potent against glutamate-induced neurotoxicity when tested in neurons. #
The synthesis of cyclic sphingosine 1,3-phosphate through photolytic methodology is described sta... more The synthesis of cyclic sphingosine 1,3-phosphate through photolytic methodology is described starting from Derythro-sphingosine. A bifunctional phosphorylating reagent, 2-cyanoethyl N,N-diisopropylchlorophosphoramidite, is used to introduce the cyclic 1,3-phosphate moiety. This procedure generates cSPP in four steps and in 36% overall yield.
1D-3,4-Dideoxyphosphatidylinositol ether lipid 2, a PI analog, was synthesized through a sequence... more 1D-3,4-Dideoxyphosphatidylinositol ether lipid 2, a PI analog, was synthesized through a sequence of protection/deprotection protocols and two Barton deoxygenation reactions, starting from L-(−)-quebrachitol. DDPIEL is 18-fold more potent than its monodeoxy counterpart DPIEL in the inhibition of PI3-K.
A series of mercaptoacetamides were designed and synthesized as novel histone deacetylase inhibit... more A series of mercaptoacetamides were designed and synthesized as novel histone deacetylase inhibitors with the aid of modeling. Their ability to inhibit HDAC activity and their effects on cancer cell growth were investigated. Some compounds exhibit better HDAC inhibitory activity than SAHA.
The synthesis and preclinical characterization of two novel, brain penetrating P2X 7 compounds wi... more The synthesis and preclinical characterization of two novel, brain penetrating P2X 7 compounds will be described. Both compounds are shown to be high potency P2X 7 antagonists in human, rat, and mouse cell lines and both were shown to have high brain concentrations and robust receptor occupancy in rat. Compound 7 is of particular interest as a probe compound for the preclinical assessment of P2X 7 blockade in animal models of neuro-inflammation.
Bioorganic & Medicinal Chemistry Letters, 1998
The synthesis of a photolyzable sphingosine 1-phosphate derivative is reported via the reaction o... more The synthesis of a photolyzable sphingosine 1-phosphate derivative is reported via the reaction of N-(tert-butoxycarbonyl)-2-N,3-O-isopropylidenesphingosine7 and bis(α-methyl-o-nitrobenzyl) N,N-diisopropyl-phosphoramidite. Stimulation of DNA synthesis upon illumination of caged SPP-loaded cells is also described.
Frontiers in cellular neuroscience, 2014
Rett syndrome (RTT) is a neurodevelopmental disorder caused by loss-of-function mutations in the ... more Rett syndrome (RTT) is a neurodevelopmental disorder caused by loss-of-function mutations in the transcriptional modulator methyl-CpG-binding protein 2 (MECP2). One of the most prominent gene targets of MeCP2 is brain-derived neurotrophic factor (Bdnf), a potent modulator of activity-dependent synaptic development, function and plasticity. Dysfunctional BDNF signaling has been demonstrated in several pathophysiological mechanisms of RTT disease progression. To evaluate whether the dynamics of BDNF trafficking is affected by Mecp2 deletion, we analyzed movements of BDNF tagged with yellow fluorescent protein (YFP) in cultured hippocampal neurons by time-lapse fluorescence imaging. We found that both anterograde and retrograde vesicular trafficking of BDNF-YFP are significantly impaired in Mecp2 knockout hippocampal neurons. Selective inhibitors of histone deacetylase 6 (HDAC6) show neuroprotective effects in neurodegenerative diseases and stimulate microtubule-dependent vesicular tra...
Nature communications, 2013
Responsible for nearly two million deaths each year, the infectious disease tuberculosis remains ... more Responsible for nearly two million deaths each year, the infectious disease tuberculosis remains a serious global health challenge. The emergence of multidrug- and extensively drug-resistant strains of Mycobacterium tuberculosis confounds control efforts, and new drugs with novel molecular targets are desperately needed. Here we describe lead compounds, the indoleamides, with potent activity against both drug-susceptible and drug-resistant strains of M. tuberculosis by targeting the mycolic acid transporter MmpL3. We identify a single mutation in mmpL3, which confers high resistance to the indoleamide class while remaining susceptible to currently used first- and second-line tuberculosis drugs, indicating a lack of cross-resistance. Importantly, an indoleamide derivative exhibits dose-dependent antimycobacterial activity when orally administered to M. tuberculosis-infected mice. The bioavailability of the indoleamides, combined with their ability to kill tubercle bacilli, indicates ...
Alzheimer's research & therapy, 2014
Tau pathology is associated with a number of age-related neurodegenerative disorders. Few treatme... more Tau pathology is associated with a number of age-related neurodegenerative disorders. Few treatments have been demonstrated to diminish the impact of tau pathology in mouse models and none are yet effective in humans. Histone deacetylase 6 (HDAC6) is an enzyme that removes acetyl groups from cytoplasmic proteins, rather than nuclear histones. Its substrates include tubulin, heat shock protein 90 and cortactin. Tubastatin A is a selective inhibitor of HDAC6. Modification of tau pathology by specific inhibition of HDAC6 presents a potential therapeutic approach in tauopathy. We treated rTg4510 mouse models of tau deposition and non-transgenic mice with tubastatin (25 mg/kg) or saline (0.9%) from 5 to 7 months of age. Cognitive behavior analysis, histology and biochemical analysis were applied to access the effect of tubastatin on memory, tau pathology and neurodegeneration (hippocampal volume). We present data showing that tubastatin restored memory function in rTg4510 mice and revers...
Journal of Medicinal Chemistry, 1993
Page 1. J. Med. Chem. 1993,36,39753977 397s Methoxylation of Cocaine Reduces Binding Affinity and... more Page 1. J. Med. Chem. 1993,36,39753977 397s Methoxylation of Cocaine Reduces Binding Affinity and Produces Compounds of Differential Binding and Dopamine Uptake Inhibitory Activity: Discovery of a Weak Cocaine Antagonist ...
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Papers by alan kozikowski