Parallel solution-phase synthesis and general biological activity of a uridine antibiotic analog library

Article abstract of DOI:10.1021/co4001452

A small library of ninety four uridine antibiotic analogs was synthesized, under the Pilot Scale Library (PSL) Program of the NIH Roadmap initiative, from amine 2 and carboxylic acids 33 and 77 in solution-phase fashion. Diverse aldehyde, sulfonyl chloride, and carboxylic acid reactant sets were condensed to 2, leading after acid-mediated hydrolysis, to the targeted compounds 3-32 in good yields and high purity. Similarly, treatment of 33 with diverse amines and sulfonamides gave 34-75. The coupling of the amino terminus of d-phenylalanine methyl ester to the free 5′-carboxylic acid moiety of 33 followed by sodium hydroxide treatment led to carboxylic acid analog 77. Hydrolysis of this material gave analog 78. The intermediate 77 served as the precursor for the preparation of novel dipeptidyl uridine analogs 79-99 through peptide coupling reactions to diverse amine reactants. None of the described compounds show significant anticancer or antimalarial acivity. A number of samples exhibited a variety of promising inhibitory, agonist, antagonist, or activator properties with enzymes and receptors in primary screens supplied and reported through the NIH MLPCN program.

Full text of DOI:10.1021/co4001452

Research Article
pubs.acs.org/acscombsci
Parallel Solution-Phase Synthesis and General Biological Activity of a
Uridine Antibiotic Analog Library
Omar Moukha-chafiq* and Robert C. Reynolds†
Southern Research Institute, Drug Discovery Division, Birmingham, Alabama 35205, United States
S
* Supporting Information
ABSTRACT: A small library of ninety four uridine antibiotic analogs was synthesized, under the Pilot Scale Library (PSL)
Program of the NIH Roadmap initiative, from amine 2 and carboxylic acids 33 and 77 in solution-phase fashion. Diverse
aldehyde, sulfonyl chloride, and carboxylic acid reactant sets were condensed to 2, leading after acid-mediated hydrolysis, to the
targeted compounds 3−32 in good yields and high purity. Similarly, treatment of 33 with diverse amines and sulfonamides gave
34−75. The coupling of the amino terminus of D-phenylalanine methyl ester to the free 5′-carboxylic acid moiety of 33 followed
by sodium hydroxide treatment led to carboxylic acid analog 77. Hydrolysis of this material gave analog 78. The intermediate 77
served as the precursor for the preparation of novel dipeptidyl uridine analogs 79−99 through peptide coupling reactions to
diverse amine reactants. None of the described compounds show significant anticancer or antimalarial acivity. A number of
samples exhibited a variety of promising inhibitory, agonist, antagonist, or activator properties with enzymes and receptors in
primary screens supplied and reported through the NIH MLPCN program.
KEYWORDS: uridine antibiotic analogs, nucleoside peptides, specific or general biological activities
propensity to enter numerous nucleoside metabolic pathways
and cause general toxicity through inhibition of DNA and RNA
metabolism. On the other hand, there are copious examples of
relatively simple to complex nucleosides that exhibit diverse
alternative mechanisms of action.3,4 Natural nucleoside anti-
biotics, for example, demonstrate potent and specific activities
such as protein synthesis inhibition, glycosyltransferase
inhibition and methyltransferase inhibition, among others.2−6
More recently, there has been a trend to develop approaches
for the synthesis and screening of this exciting class of
compounds, which do not exhibit typical broad antimetabolite
activities based on nucleoside phosphorylation and incorpo-
ration into nucleoside metabolic pathways. Among the
nucleoside antibiotics are numerous examples of 5′-substituted
peptidyl analogs modified with a diversity of amino acids, and
there has been a great deal of interest in the continued isolation
and synthesis of nucleoside amino acids and peptides.7−10
Herein, our present report is dedicated to the synthesis of a
small library of peptidyl uridine compounds generally inspired
by several bioactive natural nucleoside antibiotics including the
mureidomycins,11 muramycins,12 polyoxins (nikkomycin and
tunicamycin),4 and capuramycin.4
INTRODUCTION
■
The structural complexity and varied three-dimensional
characteristics of the natural products have been key elements
behind their propensity to produce wide ranging and
interesting biological activities. As such, the natural products
have been a crucial resource for probing biology and
metabolism with the goal of identifying new targets and leads
for drug discovery, and a large portion of the current anti-
infective and anticancer drugs are derived from natural
sources.1 Among these, nucleosides and nucleoside antibiotics
show a variety of interesting biological activities resulting in
numerous active drugs that are used clinically as anticancer,
antiviral and antifungal agents.
Although nucleosides are excellent synthetic templates for
diversity-oriented synthesis to produce novel and richly
substituted small molecules with unique directionally oriented
groups to probe biological surfaces, they are relatively poorly
represented in commercial and public compound libraries.
Furthermore, a number of robust approaches are available, both
historically and more recently using automated chemistry, that
allow rapid preparation of small libraries of highly pure unique
nucleosides.2 Hence, it has been our goal to produce new
libraries based on nucleoside templates for internal and external
screening, particularly through the NIH Roadmap Program and
the Molecular Libraries Probe Production Centers Network
(MLPCN). Traditional nucleosides with an available 5′-
hydroxyl that can enter nucleoside metabolic pathways,
however, are problematic as biological probes due to their
Most syntheses of nucleoside peptides have involved either
the coupling of an amino or hydroxyl group of a nucleoside to
Received: November 15, 2013
Revised: February 17, 2014
© XXXX American Chemical Society
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a
Scheme 1
a
(i) (a) TsCl, pyridine; (b) NaN3, DMF, 50 °C. (ii) NH4HCO2, Pd−C 10%, MeOH. (iii) R = a part f rom an aldehyde/MeOH, 0−40 °C, NaBH4;
R = a part from amino acid/HATU, DIEA, CH3CN; R = a part from sulfonyl chloride/DMF, CsCO3. (iv) 50% HCO2H, 70 °C. (v) TEMPO-
iodobenzene diacetate. (vi) R1 = amine derivative, HATU, DIEA, CH3CN or R1 = sulfonamide, DCC, DMAP, CH2Cl2.
a
Scheme 2
a
(i) D-Phenylalanine, HATU, DIEA; (ii) NaOH, dioxane; (iii) (a) R = amine derivative, HATU, DIEA, CH3CN, (b) 50% HCO2H.
the carboxyl group of a blocked amino acid, or displacement of
a leaving group on a nucleoside by the amino group of an
amino acid. Also, oxidation of the 5′-hydroxymethylene of
nucleosides to 5′-carboxylates is an essential step in the
preparation of a number of biologically active peptides.12−15
With these approaches in mind, we have designed and prepared
diverse nucleoside antibiotic-like small molecule libraries under
the PSL program of the NIH Roadmap Initiative to probe
specific or general biological activities. Very recently, we have
reported an initial phase of this program and certain analogs
have shown interesting and diverse biological activities in
preliminary MLPCN screening.16 In continuation of this effort,
we now report a facile synthesis of a novel uridine analog
library derived from amine 2 and carboxylic acid intermediates
33 and 77 (Schemes 1 and 2) using parallel solution phase
chemistry.
Both 2 and 33 are suitable precursors for the synthesis of a
variety of biologically active nucleoside analogs12−27 dating
back to the first report describing the structures and synthesis
of polyoxin analogs.28 Hence, the 5′-amino and 5′-carboxylic
acids groups of the nucleoside ribose moiety of 2 and 33 as well
the carboxylic acid group of 77 were chosen as three sites of
diversification through robust reductive amination or sulfona-
tion reactions as well as current and robust peptide coupling
chemistry to prepare the target library of analogs 3−99
(Schemes 1 and 2). The resulting nucleoside peptide library
was expected to show reasonable stability to dissolution, storage
and screening as evidenced for similar aminoacyl functions
found in various nucleoside antibiotics such as puromycin,
gougerotin, amicetin, and blasticidin S, all known inhibitors of
protein synthesis. In general, to allow the efficient and relatively
larger scale preparation of small molecule libraries, solid or
solution-phase organic synthesis has been adapted for use with
a variety of automated equipment such as liquid handlers, and
techniques, such as the fluorous-tag approach and solid-phase
extraction.
For our approach, we chose to use solution-phase organic
synthesis due to several factors. First, there are a variety of
robust reactions for both reductive amination and peptide bond
forming reactions that lead to relatively pure products in high
yields while precluding difficult purification of products. Hence,
we felt that a solid phase approach to improve yields via reagent
cycling as well as purity through reaction efficiency and release
of purified material from a solid substrate was not necessary.
Furthermore, our funded grant required repositing approx-
imately 20 mg of material with the MLSMR, as well as a tacit
commitment to supply additional material to interested
researchers upon request. Hence, we targeted 50−100 mg of
pure product to be able to fulfill this request as well as to
maintain a supply of material for internal screening purposes.
The ease and speed of the reported reactions, purification and
good yields certainly justifies our choice although we would not
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Figure 1. Structures of compounds 3−32.
Figure 2. Structures of compounds 34−76.
preclude solid phase approaches for further development of this
chemistry.
reactions were accomplished on a Radleys 12-place carousel
reaction station at room temperature, although occasionally
reactions were facilitated with less soluble aldehydes by
warming for the first ten minutes at 40 °C. The resulting
aldimines were carefully treated in situ with solid sodium
borohydride for one-half hour and the reaction was then
preadsorbed and dried on silica gel without further workup
followed by automated flash chromatography purification.
Similarly, direct acid-mediated deprotection of the acetonide
protecting group using 50% formic acid furnished the desired
final compounds 3−23 (Figure 1) in good yields.
Reductive amination is an efficient method that is readily
adaptable to parallel format and, hence, we adapted this
reaction to couple compound 2, synthesized in three steps
(Scheme 1) starting from 1 according to the modified reported
method,26 with twenty-one commercially available aldehydes.
Successful couplings were achieved in methanol in the presence
of molecular sieves to efficiently drive intermediate imine
formation. It must be noted that the use of molecular sieves was
crucial in terms of yield improvement and reaction time. The
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Table 1. Examples from PubChem Bioactivity Analysis (Primary Screening)
compound
SID (sample identification number)
134215029
56, 74, and 71 121286507, 134215027, and 134215024
biological activity
agonist of the DAF-12 from the parasite H. glycines
inhibitors of Dengue virus 2 by using the cytopathic effect assay
69
54
124753399
active in an assay that monitors the cell−cell fusion activity of HIV-1 Envs with a firefly luciferase
readout
33
activator of alpha dystroglycan glycosylation.
48 and 49
121286505 and 121286489
121286489
inhibitors of the orphan nuclear receptor subfamily 0, group B, member 1 (DAX1; NR0B1)
inhibitor of Crimean−Congo Hemorrhagic Fever viral ovarian tumor domain protease
identified as a positive allosteric modulators of the human cholinergic receptor, muscarinic 4
agonists of the mouse 5-hydroxytryptamine (serotonin) receptor 2A
inhibitor of protein arginine methyltransferase 1
49
57
121286503
40 and 64
121286502 and 121286496
121286501
51
inhibitor of microRNA-mediated mRNA deadenylation
modulator of interaction between CendR and NRP-1
3, 7, 27, and 65 93577277, 93577279, 92764715, and
D3 dopamine receptor antagonist
121286497
3
93577277
inhibitor of hepatitis C virus (HCV) with an IC50 of 6.3 μM
inhibitor of human tyrosyl-DNA phosphodiesterase 1
inhibitor of sentrin-specific protease 8
16 and 22
121284933 and 121284939
121284937
9
15
28
6
121284934
inhibitor of RAD52 protein
92764714
PAX8 inhibitor using PAX8 luciferase reporter gene assay
activator (reactivators) of BRM function
92764711
activator of methionine sulfoxide reductase A
inhibitor of HIV-1 virion infectivity factor protein
4
92764709
To achieve our small libraries 24−32 (Figure 1), 34−75
(Figure 2), and 79−99 (Scheme 2), a solution-based
methodology to efficiently generate our library was pursued.
The 24-position MiniBlock XT solution phase vessel was
utilized. The reaction vessel chosen was a 17 × 110 mm test
tube carousel because of its compatibility with our Tecan
automated liquid handler (dispensation, retraction, and
aspiration) and a Genevac evaporator. Thus, synthesis of
sulfonylamide uridine analogs 24−29 (Figure 1) was achieved
by reacting intermediate 2 with six sulfonyl chlorides. The
reactions were carried out in N,N-dimethylformamide (DMF)
at room temperature using cesium carbonate as base followed
by hydrolysis of the isopropylidene blocking groups as
described above. Peptide coupling of 2 to three amino acid
derivatives using HATU [(2-(7-aza-1H-benzotriazole-1-yl)-
1,1,3,3-tetramethyluronium hexafluorophosphate] (1 equiv)
and N,N-diisoproplyethylamine (DIPEA, 1.5 equiv) in
acetonitrile for three hours furnished, after direct acid-mediated
deprotection, the desired amide compounds 30−32 in good
yields. The same conditions were applied to prepare amides
34−68 (Figure 2) from intermediate 33 which was synthesized
in 88% yield according to the method previously described29
(Scheme 1). For the preparation of sulfonamide analogs 69−75
(Figure 2), we found that the combination of dicyclohex-
ylcarbodiimide (DCC) and one full equivalent of DMAP in
methylene chloride gave facile coupling between carboxylic acid
33 and seven sulfonamides.
All the synthesized analogs were characterized by proton
NMR, HPLC, and mass analysis. Their purity was found to
range from 90 to 100% and the average purity was 97%.
BIOLOGICAL EVALUATION
■
Compounds 3−32, 34−75, and 78−99 were screened in vitro
against human brain tumor and leukemia cell lines at a fixed
concentration of 8 μM. Only compound 66 showed modest
toxicity in these cells with an inhibition of: 75%, 66%, 39% and,
43% for brain tumor and leukemia (Jurkat, NALM-16, Raji and
Reh cells) respectively. Compound 44 was found to have a
slight inhibition (47%) when all synthesized compounds were
screened against the malaria strain 3D7 of Plasmodium
falciparum at a fixed concentration of 7 μM. In addition, the
synthesized analog library has been submitted in the MLPCN
to be screened against a wide range of biological assays (see
www.ncbi.nlm.nih.gov/pcsubstance search term Robert Rey-
nolds). Certain analogs (Table 1) exhibited a variety of
interesting activities in primary screens. For example,
compounds 3, 7, 27, and 65 were found to be antagonists of
the D3 dopamine receptor which represents a very important
target for the treatment of several neuropsychiatric disorders.
Compound 3 was also identified as an inhibitor of hepatitis C
virus with an IC50 of 6.3 μM. Analogs 56, 71, and 74 were
identified as inhibitors of dengue virus type 2. Protein arginine
methyltransferase 1 (PRMT1) activity has been associated with
cardiovascular, malignant, infectious, and autoimmune disease,
and; quinoline carboxamide 51 was active as a PRMT1
inhibitor in a high-throughput assay for PRMT1-specific
inhibition. The same compound was identified as an inhibitor
of microRNA-mediated mRNA deadenylation by a fluorescence
polarization assay. Compound 51 was also active as a
modulator of the interaction between “C-end Rule” (CendR)
peptides and Neuropilin-1 (NRP-1), which is a pleiotropic cell
surface receptor with multiple ligands that plays an essential
role in angiogenesis, cardiovascular development, regulation of
vascular permeability and development of the nervous system.
When 33 was coupled to D-phenylalanine methyl ester, 76
(Scheme 2) was formed in 81% yield. Saponification with
NaOH gave carboxylic acid intermediate 77, and subsequent
treatment with 50% formic acid quantitatively afforded final
nucleoside analog 78. The carboxylic acid group of 77 was
designed as a site of further diversification through peptide
coupling chemistry to prepare the targeted compounds 79−99
(Scheme 2) following the same conditions described for 30−
32.
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BIOLOGICAL ASSAYS
■
The antitumor assays were performed following procedures
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using the protocol published by Guiguemde et al.31
CONCLUSION
■
A general automated solution-based methodology from three
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synthesize a 94-membered library. Equipment such as a
multichannel liquid handler, vacuum centrifuge and automated
chromatography allowed the automation of solution-phase
chemistry and assisted in the preparation of high quality
products. No marked antimalarial or anticancer activity was
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ASSOCIATED CONTENT
* Supporting Information
Additional material as described in the text. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
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(16) Moukha-chafiq, O.; Reynolds, R. C. Parallel solution-phase
synthesis of an adenosine antibiotic analog library. ACS Comb. Sci.
2013, 15, 147−152.
(17) Xiuling, C.; Pallab, P.; Koichi, N.; Lanen, V.; Steven, G. V. L.
Biosynthetis origin and mechanism of formation of the aminoribosyl
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AUTHOR INFORMATION
Corresponding Author
*E-mail: moukhachafiq@southernresearch.org.
■
Present Address
†Robert C. Reynolds: Department of Chemistry, University of
Alabama at Birmingham, Birmingham, AL 35294
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This investigation was supported by NIH Grant 1P41
GM086163-01 (Pilot-Scale Libraries Based on Nucleoside
Templates for the ML Initiative, Robert C. Reynolds, P.I.).
We thank James M. Riordan, Jackie Truss, Mark Richardson
and David Poon of the Molecular and Spectroscopy Section of
Southern Research Institute for analytical and spectral data. We
also thank Kip Guy and Anang Shelat at St. Jude for preliminary
single dose screening data for human brain tumor, leukemia
and malaria cell lines.
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