α,α-Difluoro-β-ketophosphonates on a tetraazamacrocyclic platform: Synthesis and inhibitory activity against protein tyrosine phosphatases
The present study offers a new approach for designing inhibitors of protein tyrosine phosphatases. We have synthesized the cyclam derivatives with α,α-difluoro-β-ketophosphonate fragments covalently attached to tetraazamacrocyclic scaffold, which is known to be of medical interest. The obtained fu...
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Видавничий дім "Академперіодика" НАН України
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irk-123456789-882602015-11-12T03:02:19Z α,α-Difluoro-β-ketophosphonates on a tetraazamacrocyclic platform: Synthesis and inhibitory activity against protein tyrosine phosphatases Khavrienko, D.I. Kobzar, O.L. Shevchuk, M.V. Romanenko, V.D. Kobelev, S.M. Averin, A.D. Beletskaya, I.P. Vovk, A.I. Kukhar, V.P. Хімія The present study offers a new approach for designing inhibitors of protein tyrosine phosphatases. We have synthesized the cyclam derivatives with α,α-difluoro-β-ketophosphonate fragments covalently attached to tetraazamacrocyclic scaffold, which is known to be of medical interest. The obtained functionalized macrocycles were evaluated as inhibitors of PTP1B, TC-PTP, CD45, and other protein tyrosine phosphatases. Запроновано новий пiдхiд до розробки iнгiбiторiв протеїнтирозинфосфатаз. Синтезовано похiднi цикламу з α,α-дифторо-β-кетофосфонатними фрагментами, ковалентно зв’язаними з тетраазамакроциклiчною платформою. Отриманi функцiоналiзованi макроцикли було дослiджено як iнгiбiтори PTP1B, TC-PTP, CD45 та iнших протеїнтирозинфосфатаз. Предложен новый поход к разработке ингибиторов протеинтирозинфосфатаз. Синтезированы производные циклама с α,α-дифтор-β-кетофосфонатными фрагментами, ковалентно связанными с тетраазамакроциклической платформой. Полученные функционализированные макроциклы были изучены в качестве ингибиторов PTP1B, TC-PTP, CD45 и других протеинтирозинфосфатаз. 2014 Article α,α-Difluoro-β-ketophosphonates on a tetraazamacrocyclic platform: Synthesis and inhibitory activity against protein tyrosine phosphatases / D.I. Khavrienko, O.L. Kobzar, M.V. Shevchuk, V.D. Romanenko, S.M. Kobelev, A.D. Averin, I.P. Beletskaya, A.I. Vovk, V.P. Kukhar // Доповiдi Нацiональної академiї наук України. — 2014. — № 9. — С. 109-115. — Бібліогр.: 15 назв. — англ. 1025-6415 http://dspace.nbuv.gov.ua/handle/123456789/88260 547.241+577.152.3 en Доповіді НАН України Видавничий дім "Академперіодика" НАН України |
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Хімія Хімія |
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Хімія Хімія Khavrienko, D.I. Kobzar, O.L. Shevchuk, M.V. Romanenko, V.D. Kobelev, S.M. Averin, A.D. Beletskaya, I.P. Vovk, A.I. Kukhar, V.P. α,α-Difluoro-β-ketophosphonates on a tetraazamacrocyclic platform: Synthesis and inhibitory activity against protein tyrosine phosphatases Доповіді НАН України |
| description |
The present study offers a new approach for designing inhibitors of protein tyrosine phosphatases. We have synthesized the cyclam derivatives with α,α-difluoro-β-ketophosphonate fragments
covalently attached to tetraazamacrocyclic scaffold, which is known to be of medical interest.
The obtained functionalized macrocycles were evaluated as inhibitors of PTP1B, TC-PTP,
CD45, and other protein tyrosine phosphatases. |
| format |
Article |
| author |
Khavrienko, D.I. Kobzar, O.L. Shevchuk, M.V. Romanenko, V.D. Kobelev, S.M. Averin, A.D. Beletskaya, I.P. Vovk, A.I. Kukhar, V.P. |
| author_facet |
Khavrienko, D.I. Kobzar, O.L. Shevchuk, M.V. Romanenko, V.D. Kobelev, S.M. Averin, A.D. Beletskaya, I.P. Vovk, A.I. Kukhar, V.P. |
| author_sort |
Khavrienko, D.I. |
| title |
α,α-Difluoro-β-ketophosphonates on a tetraazamacrocyclic platform: Synthesis and inhibitory activity against protein tyrosine phosphatases |
| title_short |
α,α-Difluoro-β-ketophosphonates on a tetraazamacrocyclic platform: Synthesis and inhibitory activity against protein tyrosine phosphatases |
| title_full |
α,α-Difluoro-β-ketophosphonates on a tetraazamacrocyclic platform: Synthesis and inhibitory activity against protein tyrosine phosphatases |
| title_fullStr |
α,α-Difluoro-β-ketophosphonates on a tetraazamacrocyclic platform: Synthesis and inhibitory activity against protein tyrosine phosphatases |
| title_full_unstemmed |
α,α-Difluoro-β-ketophosphonates on a tetraazamacrocyclic platform: Synthesis and inhibitory activity against protein tyrosine phosphatases |
| title_sort |
α,α-difluoro-β-ketophosphonates on a tetraazamacrocyclic platform: synthesis and inhibitory activity against protein tyrosine phosphatases |
| publisher |
Видавничий дім "Академперіодика" НАН України |
| publishDate |
2014 |
| topic_facet |
Хімія |
| url |
http://dspace.nbuv.gov.ua/handle/123456789/88260 |
| citation_txt |
α,α-Difluoro-β-ketophosphonates on a tetraazamacrocyclic platform: Synthesis and inhibitory activity against protein tyrosine phosphatases / D.I. Khavrienko, O.L. Kobzar, M.V. Shevchuk, V.D. Romanenko, S.M. Kobelev, A.D. Averin, I.P. Beletskaya, A.I. Vovk, V.P. Kukhar // Доповiдi Нацiональної академiї наук України. — 2014. — № 9. — С. 109-115. — Бібліогр.: 15 назв. — англ. |
| series |
Доповіді НАН України |
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УДК 547.241+577.152.3
D. I. Khavrienko, O. L. Kobzar, M. V. Shevchuk, V. D. Romanenko,
S. M. Kobelev, A. D. Averin, Academician of the RAS I. P. Beletskaya,
Corresponding Member of the NAS of Ukraine A. I. Vovk,
Academician of the NAS of Ukraine V. P. Kukhar
α,α-Difluoro-β-ketophosphonates on a tetraazamacrocyclic
platform: Synthesis and inhibitory activity against protein
tyrosine phosphatases
The present study offers a new approach for designing inhibitors of protein tyrosine phosphata-
ses. We have synthesized the cyclam derivatives with α,α-difluoro-β-ketophosphonate fragments
covalently attached to tetraazamacrocyclic scaffold, which is known to be of medical interest.
The obtained functionalized macrocycles were evaluated as inhibitors of PTP1B, TC-PTP,
CD45, and other protein tyrosine phosphatases.
The growing awareness of a critical role of protein tyrosine phosphatases (PTPs) in the pathology
of a number of disorders such as type 2 diabetes, obesity and cancer has stimulated significant
interest in the search for potent and selective PTP inhibitors [1–2]. In the previous studies, one
of the directions in designing the inhibitors has focused on the synthesis of enzymatically stable
phosphotyrosine mimics (pTyr) which contain the fragments of (phosphonomethyl)phenylalanine
(Pmp) 1a and its fluoro-substituted analogues 1b, c [3–6]. However, there is a limitation in the
development of the low molecular PTP inhibitors due to several problems including the selectivity
and cell permeability. Therefore, the search for new pTyr mimetics is needed which facilitate the
design of drug-like PTP inhibitors as therapeutic agents is needed.
Efficient PTP inhibitors were shown to possess, besides a phosphate-mimicking component,
additional structure motifs that provide interaction with the enzyme surface beyond the catalytic
pocket. This implies that the design of PTP inhibitors should be based on the search for the
molecules containing not only a phosphotyrosine mimetic moiety but also a suitable scaffold for
the binding outside the catalytic site. From this viewpoint, the attachment of the difluorome-
thylenphosphonate [7, 8] and α,α-difluoro-β-ketophosphonate [9] groups to various scaffolds is of
considerable interest to create the novel pTyr surrogates and to evaluate their biological activity.
As a part of our work on identifying the novel PTP inhibitors [10], we now report the synthesis
of (HO)2P(O)CF2C(O)-functionalized tetraazamacrocycles using 1,4,8,11-tetraazacyclotetrade-
cane (cyclam) as a molecular platform. To the best of our knowledge, the cyclic polyamines have
© D. I. Khavrienko, O.L. Kobzar, M. V. Shevchuk, V.D. Romanenko, S.M. Kobelev, A.D. Averin,
I. P. Beletskaya, A. I. Vovk, V.P. Kukhar, 2014
ISSN 1025-6415 Доповiдi Нацiональної академiї наук України, 2014, №9 109
not been used in the development of PTP inhibitors, although they have a great potential in
the design of contrast agents for magnetic resonance imaging (MRI) and pharmaceuticals with
anti-viral (HIV) and anti-tumor activity [11].
Experimental. Methods of the synthesis of cyclam derivatives. N1, N4, N8, N11-tet-
rakis[1′-oxo-2′,2′-difluoro-2′-(diethylphosphono)ethyl]-1,4,8,11-tetraazacyclotetradecane (1a). Di-
fluoro(diethoxyphosphoryl)acetyl chloride (4.02 g, 16 mMol) was added to a solution
of 1,4,8,11-tetraazacyclotetradecane (0.80 g, 4 mMol) and diisopropylethylamine (2.07 g, 16
mMol) in dry CH2Cl2 (70 ml) at 0 ◦C. The resulting solution was stirred at 0 ◦C (1 h) and
then at 20 ◦C (10 h). The reaction mixture was washed with the aqueous solution of NaHCO3
(20 ml) and then with water (2×20 ml). The organic phase was dried (Na2SO4) and concentrated
by rotary evaporation to give a white powder. The product was treated with dry acetonitrile, the
precipitate was filtered off and placed under high vacuum for 3 h. Yield 3.0 g (71%). 1H NMR
(CDCl3): δ = 1.20–1.35 (m, 24H, CH3), 1.82–1.95 (m, 4H, CCH2C), 3.45–4.87 (m, 16H, CH2N),
4.25–4.37 (m, 16H, OCH2).
19F NMR (CDCl3): δ = −109.6 (m). 31P NMR (CDCl3): δ = 4.1
(m). Anal. Calcd. for C34H60F8N4O16P4: N, 5.30%; P, 11.72%. Found: N, 5.56%; P, 11.40%.
N1, N4, N8, N11-tetrakis[1′-oxo-2′,2′-difluoro-2′-(phosphono)ethyl]-1,4,8,11-tetraazacyclotet-
radecane (2a). To a solution of 1a (0.2 mMol, 1 eq) in MeCN (5 ml) bromotrimethylsilane (3.2
mMol, 16 eq) was added. The resulting solution was stirred at 35 ◦C overnight. Solvent was
evaporated, and the residue was treated with MeOH (3 ml). The mixture was stirred at 20 ◦C
for 15 min, and the product was precipitated by adding acetonitrile (3 ml). Solid was filtered,
washed with acetonitrile and dried under vacuum at 20 ◦C for 3 h to yield 2a as a colorless solid
in 50% yield. 1H NMR (CDCl3): δ = 1.75–2.05 (m, 4H, CCH2C), 3.58–3.77 (m, 16H, CH2N).
19F NMR (CDCl3): δ = −109.7 (m, 2JPF ∼ 90 Hz). 31P NMR (CDCl3): δ = 0.3 (m).
Compounds 1b-d and 2b-d were prepared in analogy to 1a and 2a. All new compounds have
been fully characterized. Synthesis and characterization of N1, N8-bis(2-naphthyl)cyclam, used
to obtain compounds 1d and 2d, have been described earlier [12].
N1, N8-Dibenzyl-N 4, N11-bis(3-carboxymethylbenzyl)-1,4,8,11-tetraazacyclo-tetradecane (3).
Methyl 3-(bromomethyl)benzoate (0.44 g, 1.76 mMol) and 1,8-dibenzylcyclam (0.30 g, 0.8 mMol)
were dissolved in dry DMF (5 ml). Finely powdered K2CO3 (0.69 g, 5 mMol) and catalytic
amounts of dibenzo-18-crown-6 (0.007 g, 0.02 mMol) and KI (0.033 g, 0.2 mMol) were added
to this solution. The resulting mixture was stirred at 100 ◦C for 24 h. After cooling to r. t.
the reaction mixture was poured into water (50 ml) and acidified with HCl to pH 3–4. The
precipitate was filtered and co-evaporated with EtOH to dryness. After the purification by flash
chromatography (EtOAc/hexane 1 : 3 : 0.6), the product was obtained as colorless solid. Yi-
eld 0.27 g (49%). 1H NMR (CDCl3): δ = 1.68 (m, 4H, cyclam), 2.38–2.54 (m, 16H, cyclam),
3.31 (s, 8H, NCH2Ar), 3.79 (s, 6H, CO2CH3), 7.08–7.25 (m, 12H, Ar), 7.41 (d, 3JH−H= 7.3, 2H,
Ar), 7.82 (d, 3JH−H = 7.3, 2H, Ar), 7.95 (s, 2H, Ar) ppm; MS-ESI pos: 678 (10%, M + H+),
339 (100%, M + 2H+).
N1,N8-Dibenzyl-N 4,N11-bis{3-[1′-oxo-2′,2′-difluoro-2′-(diethylphosphono)-ethyl]benzyl}-1,4,
8,11-tetraazacyclotetradecane (4). To a suspension of cerium(III) chloride (0.211 g, 0.89 mMol)
in 8 ml of THF diisopropylamine (0.091 g, 0.9 mMol) was added. The mixture was cooled to
−78 ◦C and a solution of 1.6 M n-butyllithium (0.54 ml, 0.86 mMol) was added. The mixture
was allowed to warm to −40 ◦C in 40 min. Then it was cooled to −90 ◦C and a solution of
diethyl (difluoromethyl)phosphonate (0.161 g, 0.86 mMol) in 2 ml of THF was added. The mi-
xture was stirred at −90 ◦C for 1 h, then a solution of 3 (0.264 g, 0.39 mMol) in 10 ml of
THF was added. Reaction mixture was then stirred at −80 ◦C for 1 h and allowed to warm
110 ISSN 1025-6415 Reports of the National Academy of Sciences of Ukraine, 2014, №9
to −30 ◦C in 1 h. The reaction was quenched by adding NH4Cl aqueous solution. The product
was extracted with CH2Cl2 and dried over Na2SO4. The solvent was evaporated in vacuo, and
the product 4 was purified by flash chromatography (CH2Cl2/MeOH from 100 : 4 to 100 : 7).
Yield 127 mg (33%). 19F NMR (CDCl3): δ = −110.3 (d, 2JPF = 95 Hz). 31P NMR (CDCl3):
δ = 4.3 (t, 2JPF = 95 Hz).
N1, N8-Dibenzyl-N 4, N11-bis{3-[1′-oxo-2′,2′-difluoro-2′-(phosphono)ethyl]-benzyl}-1,4,8,11-
tetraazacyclotetradecane trisodium salt (5). Deprotection of phosphonate ester 4 was accompli-
shed similarly to compound 1a. Phosphonic acid was converted into its trisodium salt by di-
ssolving the acid in NaHCO3 (3 eq) aqueous solution and evaporating the resulting solution to
dryness.
Bioassay for the study of inhibitory activity. Before using in assay, the commercially
available preparations of human recombinant PTP-1B and other PTPs were diluted in buffer
solution, which contained 50 mM Bis-Tris (pH 7.2), 3 mM EDTA, 2 mM DTT, 75 mM NaCl, 30%
glycerol and 0.05% Tween-20, and stored at −70 ◦C. The system for the inhibitory effect testing
consisted of 50 mM Bis-Tris (pH 7.2), 2 mM EDTA, 1 mM DTT, 100 mM NaCl, 1% DMSO and
p-nitrophenyl phosphate as the enzyme substrate. After 5-minute incubation at 37 ◦C for PTP1B
and 30◦C for other enzymes, the reaction was initiated by adding the enzyme in a concentration
of 4–10 nM. The enzyme activity was detected at 410 nm by measuring the absorbance of
p-nitrophenol formed through enzymatic hydrolysis of the substrate.
Discussion. Scheme 1 illustrates the preparation of 1,4,8,11-tetrasubstituted cyclam 1a
containing four α,α-difluoro-β-ketophosphonate groups via the direct acylation of the tetraaza-
macrocycle with difluoro(diethoxyphosphoryl)acetyl chloride. The synthesis was performed by
adding acyl chloride to the mixture of cyclam and diisopropylethylamine in dry dichloromethane
at 0 ◦C. Subsequent trans-silylation of the phosphonate ester 1a with bromotrimethylsilane
followed by hydrolysis afforded the desired product 2a. Its molecular structure was confirmed by
analytical and spectral data. Interestingly, 19F NMR spectrum of 1a exhibited complex multi-
plet at δ-109.6 ppm and broad triplet in the proton-decoupled 31P NMR spectrum at δ4.1 ppm
(2JPF ∼ 93 Hz). Similar spectra were observed for 2a. These spectral features probably can be
explained by the existence of the compounds 1a and 2a as a mixture of structural conformers.
This conclusion is supported by the existence of tri-CF3C(O)-substituted cyclam as a mixture
conformers [13] and by the fact that, according to 19F NMR spectra, N -acylated piperazine deri-
vative (Ciprofloxacin®) containing β-keto-α, α-difluorophosphonate moiety exists as a mixture
of two stereoisomers in a ratio of 70 : 30 [14].
The inhibitory potential of compound 2a was evaluated in vitro using PTP1B, TC-PTP,
CD45, SHP2 and PTP β. The experimentally obtained IC50 values (the inhibitor concentration
necessary to inhibit the enzyme activity by 50%) were in the concentration range of 100–1200 µM
for all the PTPs. These results showed low inhibitory potency of compound 2a on the enzymes
tested.
We next investigated the synthesis and PTP inhibiting activity of the α,α-difluoro-β-keto-
phosphonate-functionalized tetraazamacrocycles derived from N1, N8-disubstituted cyclams.
The desired phosphonate derivatives 1b-d were prepared starting from dimethyl-, dibenzyl- and
di(2-naphthylmethyl)-substituted cyclams and isolated as phosphonic acids 2b-d. Molecular
structures of these compounds were confirmed by mass spectral (MS), 1H, 19F, 31P NMR, and
analytical data. It should be noted that, similarly to compound 1a, the presence of structural
conformers for compounds 1b-d was detected by 19F and 31P NMR spectra in CDCl3 at room
temperature.
ISSN 1025-6415 Доповiдi Нацiональної академiї наук України, 2014, №9 111
Scheme 1. Synthesis of β-keto-α,α-difluorophosphonate-functionalized cyclams
Compound 2b was found to be a weak inhibitor of TC-PTP with IC50 value approximately 1.1
mM. The replacement of methyl groups in 2b with benzyl or 2-naphthylmethyl groups gave
compounds 2c and 2d which showed IC50 values of 230 and 110 µM, respectively. In the case
of CD45, cyclam derivative 2d displayed IC50 value of 35 µM with a slight reduced inhibitory
activity against TC-PTP, SHP2, and PTP β. The presence of 2-naphthylmethyl groups seems
to make the derivative 2d more hydrophobic and leads to increasing the binding of the inhibitor
at the region of the active site of CD45 with nonpolar amino acid residues.
The next step in the optimization of cyclam-based PTP inhibitors was the synthesis of the
tetraazamacrocycle in which the benzyl groups serve as bridges between N4, N11-nitrogen sites
and α,α-difluoro-β-ketophosphonate moiety. Thus, we examined α,α-difluoro-β-ketophosphonate
5 derived from 1,8-dibenzylcyclam. This compound was prepared by the alkylation of 1,8-di-
benzylcyclam with methyl 3-(bromomethyl)benzoate in the presence of K2CO3 followed by ceri-
um-mediated reaction of 3 with LiCF2P(O)(OEt)2 [15]. Deprotection of the phosphonate ester 4
was achieved by transsilylation reaction with excess Me3SiBr followed by hydrolysis (Scheme 2).
The data of inhibition of PTPs demonstrated that compound 5 is able to inhibit TC-PTP with
IC50 value of 9.7 µM. This α,α-difluoro-β-ketophosphonate showed about 10-fold selectivity over
PTP1B and had practically no effect on CD45, SHP2, and PTP β activity at a concentration
of 100 µM.
Thus, the results reported here suggest that macrocyclic polyamines are promising scaffolds
for designing effective inhibitors of TC-PTP and other phosphatases, and new synthetic deri-
112 ISSN 1025-6415 Reports of the National Academy of Sciences of Ukraine, 2014, №9
Scheme 2. Synthesis of α,α-difluoro-β-ketophosphonate 5 derived from 1,8-dibenzylcyclam
vatives of cyclam might be considered as possible regulators of cellular processes controlled
by PTPs.
This study was financially supported by the State Fund of Fundamental Research of Ukraine (project
F53.3/020) and by the National Academy of Sciences of Ukraine (project 01–2/2014). The authors thank
D.Yu. Masich for the participation in the synthesis of some compounds.
ISSN 1025-6415 Доповiдi Нацiональної академiї наук України, 2014, №9 113
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Received 12.06.2014Institute of Bioorganic Chemistry
and Petrochemistry, NAS of Ukraine
Lomonosov Moscow State University,
Department of Chemistry, Moscow, Russia
Д. I. Хаврiєнко, О. Л. Кобзар, М. В. Шевчук, В.Д. Романенко,
С.М. Кобелев, А. Д. Аверiн, академiк РАН I.П. Белецька,
член-кореспондент НАН України А. I. Вовк,
академiк НАН України В.П. Кухар
α,α-Дифторо-β-кетофосфонати на тетраазамакроциклiчнiй
платформi: синтез та iнгiбiторна активнiсть по вiдношенню
до протеїнтирозинфосфатаз
Запроновано новий пiдхiд до розробки iнгiбiторiв протеїнтирозинфосфатаз. Синтезовано
похiднi цикламу з α,α-дифторо-β-кетофосфонатними фрагментами, ковалентно зв’язани-
ми з тетраазамакроциклiчною платформою. Отриманi функцiоналiзованi макроцикли було
дослiджено як iнгiбiтори PTP1B, TC-PTP, CD45 та iнших протеїнтирозинфосфатаз.
114 ISSN 1025-6415 Reports of the National Academy of Sciences of Ukraine, 2014, №9
Д.И. Хавриенко, О.Л. Кобзар, М. В. Шевчук, В.Д. Романенко,
С.М. Кобелев, А. Д. Аверин, академик РАН И.П. Белецкая,
член-корреспондент НАН Украины А. И. Вовк,
академик НАН Украины В.П. Кухар
α,α-Дифтор-β-кетофосфонаты на тетраазамакроциклической
платформе: синтез и ингибиторная активность по отношению
к протеинтирозинфосфатазам
Предложен новый поход к разработке ингибиторов протеинтирозинфосфатаз. Синтезиро-
ваны производные циклама с α,α-дифтор-β-кетофосфонатными фрагментами, ковалентно
связанными с тетраазамакроциклической платформой. Полученные функционализирован-
ные макроциклы были изучены в качестве ингибиторов PTP1B, TC-PTP, CD45 и других
протеинтирозинфосфатаз.
ISSN 1025-6415 Доповiдi Нацiональної академiї наук України, 2014, №9 115
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