Synthesis of [13C4]‐labeled 2′‐deoxymugineic acid

The phytosiderophore 2′‐deoxymugineic acid (DMA) is exuded via the root system by all grasses (including important crop plants like rice, wheat and barley) to mobilize Fe(III) from soil and improve plant Fe nutrition, crucial for high crop yields. Elucidation of the biogeochemistry of 2′‐deoxymugineic acid in the rhizosphere requires its quantification in minute amounts. To this end, ¹³C₄‐DMA was synthesized for the first time, from cheap isotopically labeled starting materials. The synthetic route utilizes l ‐allyl(¹³C₂)glycine and l ‐(2‐¹³C)azetidine (¹³C)carboxylic acid as versatile labeled building blocks. The title compound was recently used as an internal standard for analysis of soil and plant samples allowing the first accurate quantification of DMA in these matrices by means of LC‐MS/MS. It is furthermore used in tracer experiments investigating biodegradation of DMA in soil.     

Synthesis of a technetium‐99m labelled L‐tyrosine derivative with the fac‐99mTc(I)(CO)3‐core using a simple kit‐procedure

The synthesis of a novel technetium‐99m labelled derivative of L ‐tyrosine as a potential tumour imaging agent for nuclear medicine diagnosis is reported. The synthesis involved the labelling precursor fac‐[^99mTc(OH₂)(CO)₃]⁺ which was synthesized using the commercially available Isolink^®‐labelling kit and the tyrosine derivative O‐(N,N‐bis(carboxymethyl)aminoethyl)‐L ‐tyrosine trifluoroacetate. The labelled compound O‐(^99mTc(I)‐tricarbonyl‐N,N‐bis(carboxymethyl)aminoethyl)‐L ‐tyrosine was obtained in a radiochemical yield of 70–80% within 60 min with a radiochemical purity greater than 98% without any HPLC purification step. Purification was achieved merely by solid phase extraction. Chemical as well as chiral purity was determined using gradient‐ and chiral HPLC. Copyright © 2004 John Wiley & Sons, Ltd.     

Synthesis and calcium channel modulation effects of isopropyl 1,4‐dihydro‐2,6‐dimethyl‐3‐nitro‐4‐phenylpyridine‐5‐carboxylates possessing ortho‐, meta‐, and para‐CH2S(O)nMe and –S(O)nMe (n = 0–2) phenyl substituents

A group of isopropyl 1,4‐dihydro‐2,6‐dimethyl‐3‐nitro‐4‐phenylpyridine‐5‐carboxylates ( 13–15 ) possessing ortho‐, meta‐, and para‐CH₂S(O)nMe and –S(O)nMe (n = 0–2) phenyl substituents were synthesized using a modified Hantzsch reaction. Calcium channel (CC) modulating activities were determined using guinea pig ileum longitudinal smooth muscle (GPILSM) and guinea pig left atrium (GPLA) in vitro assays. This class of –CH₂S(O)nMe and –S(O)nMe (n = 0–2) compounds ( 13–15a–f ) exhibited weaker CC antagonist activity on GPILSM (IC₅₀ = > 1.1 × 10^–5 to 4.1 × 10^–6 M range) than the reference drug nifedipine (IC₅₀ = 1.4 × 10^–8 M). The oxidation state of the sulfur atom was a determinant of smooth muscle CC antagonist activity where the relative activity profile was generally thio ( 13 , ‐CH₂SMe, ‐SMe) and sulfonyl ( 15 , ‐CH₂SO₂Me, ‐SO₂Me) > sulfinyl ( 14 , ‐CH₂SOMe, ‐SOMe). The point of attachment of the phenyl substituent was a determinant of activity for the –CH₂SMe ( 13a–c ), ‐CH₂SOMe ( 14a–c ) and SOMe ( 14d–f ) isomers where the relative potency order was meta and para > ortho. Compounds in this group ( 13–15 ), unlike Bay K 8644 (EC₅₀ = 2.3 × 10^–7 M on GPILSM), did not exhibit an agonist effect on GPILSM. The meta‐CH₂SMe ( 13b ), ortho‐CH₂SMe ( 13c ), meta‐SMe ( 13e ), and ortho‐CH₂SO₂Me ( 15c ) C‐4 phenyl derivatives exhibited respectable in vitro cardiac positive inotropic activities (EC₅₀ = 1.00 × 10^–6 to 7.57 × 10^–6 M range) relative to the reference drug Bay K 8644 (EC₅₀ = 7.70 × 10^–7 M) in the GPLA assay. In contrast to Bay K 8644, which acts as an undesirable calcium channel agonist on smooth muscle (GPILSM), compounds 13b (IC₅₀ = 4.11 × 10^–6 M), 13c (IC₅₀ = 2.29 × 10^–5 M), 13e (IC₅₀ = > 1.20 × 10^–5 M) and 15c (IC₅₀ = 6.22 × 10^–6 M) exhibited a desirable simultaneous calcium channel antagonist effect on smooth muscle at a similar ( 13b , 15c ), or lower ( 13c , 13e ), concentration relative to its cardiac agonist EC₅₀ value. Model compounds such as 13b , 13c , 13e , and 15c , that exhibit dual cardioselective agonist / smooth muscle selective antagonist activities, represent a novel type of 1,4‐dihydropyridine CC modulators that offer a potential approach to drug discovery targeted toward the treatment of congestive heart failure and for use as probes to study the structure–function relationship of calcium channels. Drug Dev. Res. 51:177–186, 2000. © 2001 Wiley‐Liss, Inc.     

Novel Side‐Chain Glucosylated and Adamantylated [Asp2/Glu2]Enkephalin Analogs: Synthesis and In Vitro Growth Inhibition of Human Tumor Cells

A series of new backbone‐modified Leu‐ and Met‐enkephalin analogs ( 13 – 20 a and b ) were synthesized. Backbone manipulations involved the replacement of the Gly² residue in Tyr‐Gly‐Gly‐Phe‐Leu/Met with side‐chain glucosylated or adamantylated D /L ‐aspartic or ‐glutamic acids. The in vitro antiproliferative activity of these compounds was evaluated for several cell lines and the results were compared with the effect of Met‐enkephalin, the native opioid growth factor. The tested compounds modestly inhibited the growth of the tumor cells (20–50% inhibition at millimolar concentrations). Among the tested compounds, Tyr‐D ‐Glu(AdNH)‐Gly‐Phe‐Met ( 20b ) showed significant antiproliferative activity, somewhat more pronounced on MCF‐7 (breast carcinoma) and MOLT‐4 (lymphoblastic leukemia) cells.     

Reprofiling of full‐length phosphonated carbocyclic 2′‐oxa‐3′‐aza‐nucleosides toward antiproliferative agents: Synthesis,antiproliferative activity,and molecular docking study

A series of phosphonated carbocyclic 2 ′ ‐oxa‐3 ′ ‐aza‐nucleosides were synthesized via 1,3 dipolar cycloaddition and evaluated for their in vitro antiproliferative activity against the growth of cancer cell lines (MCF‐7, A2780, HCT116) and normal non‐transformed fibroblast (MRC5) using MTT assay. Synthesized compounds exhibited antiproliferative activity in the micromolar range. Compounds 11b showed the highest activity against MCF‐7 cells (IC₅₀ of 0.2344 μm ). Cell cycle analysis was performed for compound 11b on MCF7 cells showing arrest of cells in the S phase. Molecular docking of synthesized compounds confirmed high affinity of these compounds to two different receptors for anticancer nucleosides on dCK, namely the 1P5Z and 2ZIA, showing scores higher than the cognate ligand for all tested compounds. All synthesized compounds were evaluated according to the Lipinski, Veber, and Opera rules, and all of them passed the evaluation showing excellent features, superior to reference drugs. In addition, ADME for all the synthesized compounds was predicted through a theoretical kinetic study using the discovery studio 3.1 software.     

Synthesis of labeled acrylamide and N‐methylolacrylamide (NMA): 15N‐acrylamide, 13C‐NMA, 15N‐NMA,and 13C,15N‐NMA

Labeled derivatives of N‐methylolacrylamide (NMA) including ¹⁵N‐NMA, ¹³C‐NMA, and ¹³C,¹⁵N‐NMA were synthesized and purified. A required chemical precursor, ¹⁵N‐acrylamide, was also prepared. Reported methods for synthesizing unlabeled analogs are noted, and modifications to these methods for achieving the labeled materials are specified. Monomers were examined via ¹H, ¹³C, and ¹⁵N nuclear magnetic resonance (NMR) spectroscopy. Peak assignments and coupling constants are reported for each compound. To our knowledge, this is the first reported publication on the preparation and characterization of ¹³C‐NMA, ¹⁵N‐NMA, ¹³C,¹⁵N‐NMA, and ¹⁵N‐acrylamide. Copyright © 2005 John Wiley & Sons, Ltd.     

The synthesis of isotopically labeled (+)‐2‐aminobicyclo[3.1.0]hexane‐2,6‐carboxylic acid and its 2‐oxa‐ and 2‐thia‐analogs

As part of a program aimed at the design of conformationally constrained analogs of glutamic acid, (+)‐2‐aminobicyclo[3.1.0]hexane‐2,6‐carboxylic acid ( 1 ), identified as a highly potent, selective, group II metabotropic glutamate receptor agonist has been synthesized and studied clinically. Heterocyclic analogs of 1 were subsequently synthesized in which the C‐2 methylene has been replaced by an oxygen atom ( 2 ) or a sulfur atom ( 3 ). C‐14 labeled isotopomers of 1 , 2 and 3 have been synthesized to facilitate pre‐clinical ADME studies. A tritium labeled isotopomer of 1 was also synthesized for use in in vitro experiments. A stable labeled isotopomer of rac‐1 was prepared for use as an internal standard for bioanalytical assays. The key step in each of these syntheses was the reaction of chiral ketone 4 , 5 or 6 with K¹⁴CN/(NH₄)₂CO₃ using the Bucherer–Berg protocol. In the preparation of the stable labeled isotopomer, rac‐4 ‐[¹³ C ₂] was prepared in two steps from ethyl bromoacetate‐[UL‐¹³C₂]; subsequent reaction of rac‐4 ‐[¹³ C ₂] with K¹³CN/¹⁵NH₄Cl/Na₂CO₃, followed by hydrolysis of the hydantoin yielded rac‐1 ‐[¹³ C ₃,¹⁵ N ]. Copyright © 2005 John Wiley & Sons, Ltd.     

Design,synthesis, in silico and antiproliferative evaluation of novel pyrazole derivatives as VEGFR‐2 inhibitors

As the blockade of the VEGFR‐2 signaling pathway is a viable approach in cancer therapy, the present study focuses on a series of pyrazole based VEGFR‐2 inhibitors that were designed on the basis of the hybridization approach, supported by docking and in silico computational studies. The designed compounds were synthesized through facile synthetic methods and the structures were confirmed by ¹H NMR, ¹³C NMR, MS and elemental analysis. The compounds were screened for in vitro antiproliferative activity against the HT‐29 (human colon cancer) and MCF‐7 (human breast cancer) cell lines by MTT assay. The compounds were also studied for in vitro inhibitory activity against VEGFR‐2 kinase. Among all the tested compounds, compound 6h emerged as a potent agent in the antiproliferative study against HT‐29 and MCF‐7 cells, with IC₅₀ values of 2.36 and 6.59 μM, respectively. Moreover, the same compound exhibited the highest VEGFR‐2 inhibitory activity with an IC₅₀ value of 1.89 μM. In docking studies, the designed compounds showed similar and essential key interactions as those of known VEGFR‐2 inhibitors. The present study may lead to new molecules in the development of anticancer agents targeting VEGFR‐2.     

Synthesis,molecular modeling,in vivo study,and anticancer activity of 1,2,4‐triazole containing hydrazide–hydrazones derived from (S)‐naproxen

A new series of 1,2,4‐triazole containing hydrazide–hydrazones derived from (S)‐naproxen ( 7a–m ) was synthesized in this study. The structures of these compounds were characterized by spectral (Fourier‐transform infrared spectroscopy, ¹H‐nuclear magnetic resonance (NMR), ¹³C‐NMR, and high‐resolution electron ionization mass spectrometry) methods. Furthermore, molecular modeling of these compounds was studied on human methionine aminopeptidase‐2. All synthesized compounds were screened for anticancer activity against three prostate cancer cell lines (PC3, DU‐145, and LNCaP) using the 3‐(4,5‐dimethylthiazol‐2‐yl)‐5‐(3‐carboxymethoxyphenyl)‐2‐(4‐sulfophenyl)‐2H‐tetrazolium colorimetric method. Compound 7a showed the best activity against the PC3, DU‐145 and LNCaP cancer cell lines with IC₅₀ values of 26.0, 34.5, and 48.8 μM, respectively. Compounds 7b , 7k , and 7m showed anticancer activity against cancer cell lines PC3 and DU‐145 with IC₅₀ values of 43.0, 36.5, 29.3 μM and 49.8, 49.1, 31.6 μM, respectively. Compounds 7f and 7g showed anticancer activity against PC3 cells with IC₅₀ values of 43.4 and 34.5 μM, respectively. To assess the biodistribution in mice of IRDye800, dye‐labeled compound 7a or 100 μM of free dye was injected intravenously into the mice's tail. In vivo images were taken with in vivo imaging system spectrum device at 60, 120, 180, 240, 300, and 360 min after injection. At the end of 360 min, ex vivo studies were carried out to determine in which organs the dye was accumulated in the urogenital system. Ex vivo studies showed that the accumulation of compound 7a in the prostate is greater than that of the free dye, and it is concluded that compound 7a may be promising for the treatment of prostate cancer.     

Synthesis of 1‐(2′‐deoxy‐2′‐fluoro‐β‐D‐arabinofuranosyl)‐[Methyl‐11C]thymine ([11C]FMAU) via a Stille cross‐coupling reaction with [11C]methyl iodide

1‐(2′‐deoxy‐2′‐fluoro‐β‐D‐arabinofuranosyl)‐[methyl‐¹¹C]thymine ([¹¹C]FMAU) [¹¹C]‐ 1 was synthesised via a palladium‐mediated Stille coupling reaction of 1‐(2′‐deoxy‐2′‐fluoro‐β‐D‐arabinofuranosyl)‐5‐(trimethylstannyl)uracil 2 with [¹¹C]methyl iodide in a one‐pot procedure. The reaction conditions were optimized by screening various catalysts and solvents, and by altering concentrations and reaction temperatures. The highest yield was obtained using Pd₂(dba)₃ and P(o‐tolyl)₃ in DMF at 130°C for 5 min. Under these conditions the title compound [¹¹C]‐ 1 was obtained in 28±5% decay‐corrected radiochemical yield calculated from [¹¹C]methyl iodide (number of experiments=7). The radiochemical purity was >99% and the specific radioactivity was 0.1 GBq/μmol at 25 min after end of bombardment. In a typical experiment 700–800 MBq of [¹¹C]FMAU [¹¹C]‐ 1 was obtained starting from 6–7 GBq of [¹¹C]methyl iodide. A mixed ¹¹C/¹³C synthesis to yield [¹¹C]‐ 1 /(¹³C)‐ 1 followed by ¹³C‐NMR analysis was used to confirm the labelling position. The labelling procedure was found to be suitable for automation. Copyright © 2002 John Wiley & Sons, Ltd.     

125I‐Labeled 2‐O‐ and 3‐O‐m‐iodobenzyl,and 6‐O‐m‐iodophenyl derivatives of L‐ascorbic acid: synthesis and preliminary tissue distribution

Three ¹²⁵I‐labeled 2‐O‐ and 3‐O‐m‐iodobenzyl, and 6‐O‐m‐iodophenyl derivatives of L ‐ascorbic acid were prepared by melt exchange procedures in isolated radiochemical yields of 12–60% after HPLC purification. Biodistribution studies in tumor‐bearing mice showed very different in vivo tissue uptake properties from previous results obtained with ¹⁴C‐labeled ascorbic acid and 6‐deoxy‐6‐[¹⁸F]fluoro‐L ‐ascorbic acid. None of these seems to be suitable radioiodinated analogs of L ‐ascorbic acid for imaging study of its in vivo biochemistry. Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis of (E)‐2,3′,4,5′‐tetramethoxy[2‐11C]stilbene

In this paper, we describe the radiosynthesis of the compound (E)‐2,3′,4,5′‐tetramethoxy[2‐¹¹C]stilbene, a potential, universal tumour positron emission tomography imaging agent. The production of (E)‐2,3′,4,5′‐tetramethoxy[2‐¹¹C]stilbene was carried out via ¹¹C‐methylation of (E)‐2‐(hydroxy)‐3′,4,5′‐trimethoxystilbene by using [¹¹C]methyl trifluoromethanesulfonate ([¹¹C]methyl triflate). (E)‐2,3′,4,5′‐tetramethoxy[2‐¹¹C]stilbene was obtained with a radiochemical purity greater than 95% in a 20 ± 2% decay‐corrected radiochemical yield, based upon [¹¹C]carbon dioxide. Synthesis, purification and formulation were completed on an average of 30 min following the end of bombardment (EOB). The specific radioactivity obtained was 1.9 ± 0.6 GBq/µmol at EOB. Copyright © 2007 John Wiley & Sons, Ltd.     

Antileukemic action of novel diamine Pt(II) halogenido complexes: Comparison of the representative novel Pt(II) with corresponding Pt(IV) complex

This study presents the synthesis, characterization, and antitumor action of five new Pt(II ) halogenido, chlorido, and iodido complexes with edda type of ligands. (S,S)‐ Ethylenediamine‐N,N′‐di‐2‐(3‐cyclohexyl)propanoic acid dihydrochloride and its methyl, ethyl, and n‐propyl esters were prepared according to the previously reported procedure. All investigated complexes were characterized by IR , ESI ‐MS (¹H, ¹³C, and HMBC ) NMR spectroscopy, and elemental analysis. Their cytotoxic action was investigated in four human tumor cell lines: promyelocytic (HL ‐60) and lymphocytic (REH ) leukemia, glioma (U251), and lung carcinoma (H460). Cell viability was assessed by acid phosphatase and LDH assay, while oxidative stress and cell death parameters were analyzed by flow cytometry. The results showed that novel Pt(II ) complexes exhibited antitumor action superior to precursor ligands, with iodido complexes being more efficient than corresponding chlorido complexes. Human promyelocytic cell line (HL ‐60) was the most sensitive to antitumor action of all investigated substances and was used for investigation of the underlying mode of antileukemic action. The investigated Pt(II ) complexes showed more potent antileukemic action than corresponding Pt(IV ) complex, through induction of oxidative stress and apoptosis, evidenced by caspase (8, 9, and 3) activation and phosphatidylserine externalization.     

Synthesis of [1,3, NH2‐15N3] (5′S)‐8,5′‐cyclo‐2′‐deoxyguanosine

To facilitate NMR studies and low‐level detection in biological samples by mass spectrometry, [1,3, NH₂‐¹⁵N₃] (5′S)‐8,5′‐cyclo‐2′‐deoxyguanosine was synthesized from imidazole‐4,5‐dicarboxylic acid in 21 steps. The three ¹⁵N isotopes were introduced during the chemo‐enzymatic preparation of [1,3, NH₂‐¹⁵N₃]‐2′‐deoxyguanosine using an established procedure. The ¹⁵N‐labeled 2′‐deoxyguanosine was converted to a 5′‐phenylthio derivative, which allowed the 8‐5′ covalent bond formation via photochemical homolytic cleavage of the C–SPh bond. SeO₂ oxidation of C‐5′ followed by sodium borohydride reduction and deprotection gave the desired product in good yield. The isotopic purity of the [1,3, NH₂‐¹⁵N₃] (5′S)‐8,5′‐cyclo‐2′‐deoxyguanosine was in excess of 99.94 atom% based on liquid chromatography–mass spectrometry measurements. Copyright © 2013 John Wiley & Sons, Ltd.     

Potent Opioid Peptide Agonists Containing 4′‐[N‐((4′‐phenyl)‐phenethyl)carboxamido]phenylalanine (Bcp) in Place of Tyr

Analogues of the opioid peptides H‐Tyr‐c[d ‐Cys‐Gly‐Phe(pNO₂)‐d ‐Cys]NH₂ (non‐selective), H‐Tyr‐d ‐Arg‐Phe‐Lys‐NH₂ (μ‐selective) and dynorphin A(1‐11)‐NH₂ (κ‐selective) containing 4′‐[N‐((4′‐phenyl)‐phenethyl)carboxamido]phenylanine (Bcp) in place of Tyr¹ were synthesized. All three Bcp¹‐opioid peptides retained high μ opioid receptor binding affinity, but showed very significant differences in the opioid receptor selectivity profiles as compared with the corresponding Tyr¹‐containing parent peptides. The cyclic peptide H‐Bcp‐c[d ‐Cys‐Gly‐Phe(pNO₂)‐d ‐Cys]NH₂ turned out to be an extraordinarily potent, μ‐selective opioid agonist, whereas the Bcp¹‐analogue of dynorphin A(1‐11)‐NH₂ displayed partial agonism at the μ receptor. The obtained results suggest that the large biphenylethyl substituent contained in these compounds may engage in a hydrophobic interaction with a receptor subsite and thereby may play a role in the ligand’s ability to induce a specific receptor conformation or to bind to a distinct receptor conformation in a situation of conformational receptor heterogeneity.     

A simple convenient synthesis of l‐[4‐13C]glutamine

l ‐[4‐¹³C]Glutamine was synthesized from sodium [2‐¹³C]acetate in 12 steps and 18% overall yield. A Wittig reaction of (R)‐benzyl 4‐formyl‐2,2‐dimethyloxazolidine‐3‐carboxylate and ethyl 2‐(triphenylphosphoranylidene)[2‐¹³C]acetate prepared from d ‐serine and sodium [2‐¹³C]acetate, respectively, gave (4S)‐4‐(2‐ethoxycarbonyl[2‐¹³C]vinyl)‐2,2‐dimethyloxazolidine‐3‐carboxylic acid α,β‐isopropylidene group, oxidation of the resulting hydroxyl group to a carboxyl group and transamidation of the ester moiety gave l ‐N‐Cbz‐[4‐¹³C]glutamine (Cbz = benzyloxycarbonyl). Finally, removal of the Cbz group gave l ‐[4‐¹³C]glutamine. l ‐[4‐¹³C]Glutamine can be prepared in fewer steps and higher yield by this method compared with previously reported methods.     

13C‐ and 14C‐labelling of N‐[1‐(4‐chlorophenyl)‐1H‐pyrrol‐2‐yl‐methyleneamino] guanidinium acetate

N‐[1‐(4‐chlorophenyl)‐1H‐pyrrol‐2‐yl‐¹³C₄‐methyleneamino]guanidinium acetate has been synthesized by a four‐step procedure. This involved reduction of the Weinreb amide N,N′‐dimethyl‐N,N′‐dimethyloxybutane‐1,4‐diamide‐1,2,3,4‐¹³C₄ by Dibal‐H to give the corresponding unstable dialdehyde which is reacted in situ with 4‐chloroaniline to form 1‐(4‐chlorophenyl)‐1H‐pyrrole‐¹³C₄. This pyrrole analogue underwent a Vilsmeyer acylation with POCl₃/DMF followed by final reaction with aminoguanidine bicarbonate to produce the desired labelled compound with 99% atom ¹³C. By using DMF [α‐¹⁴C] a radio‐labelled analogue was synthesized with a specific activity of 60 mCi/mmol. Copyright © 2005 John Wiley & Sons, Ltd.     

A new approach for 11C–C bond formation: Synthesis of 17α‐(3′‐[11C]prop‐1‐yn‐1‐yl)‐3‐methoxy‐3,17β‐estradiol

A new approach for ¹¹C–C bond formation via a Sonogashira‐like cross‐coupling reaction of terminal alkynes with [¹¹C]methyl iodide was exemplified by the synthesis of 17α‐(3′‐[¹¹C]prop‐1‐yn‐1‐yl)‐3‐methoxy‐3,17β‐estradiol. The LC‐purified title compound was obtained in decay‐corrected radiochemical yields of 27–47% (n=8) based on [¹¹C]methyl iodide within 21–27 min after EOB. In a typical synthesis starting from 9.6 GBq [¹¹C]methyl iodide, 1.87 GBq of 17α‐(3′‐[¹¹C]prop‐1‐yn‐1‐yl)‐3‐methoxy‐3,17β‐estradiol was synthesized in radiochemical purity >99%. The specific radioactivity ranged between 10 and 19 GBq/µmol, and the labeling position was verified by ¹³C‐NMR analysis of the corresponding ¹³C‐labeled compound. Copyright © 2003 John Wiley & Sons, Ltd.     

X‐ray and 13C solid‐state NMR studies of N‐benzoyl‐phenylalanine

Abstract: A crystalline sample of N‐benzoyl‐dl ‐phenylalanine 1 and a polycrystalline sample of N‐benzoyl‐l ‐phenylalanine 2 were studied using ¹³C high‐resolution solid‐state NMR spectroscopy. The X‐ray structure of the dl form was established. Sample 1 crystallizes in a monoclinic form with a P2₁/c space group, a = 11.338(1) Å, b = 9.185(1) Å, c = 14.096(2) Å, β = 107.53(3)°, V = 1400(3) ų, Z = 4 and R = 0.053. The principal elements of the ¹³C chemical shift tensors δ_ii for 1 and 2 , selectively ¹³C (99%) labeled at the carboxyl groups were calculated. On the basis of ¹³C δ_ii analysis the hydrogen bonding pattern for sample 2 was deduced. Enriched samples were used to establish the intermolecular distance between chemically equivalent nuclei for 1 and spatial proximity in heterogeneous domain for 2 , employing the ODESSA pulse sequence. The consistence of the complementary approach covering X‐ray data, analysis of the ¹³C δ_ii parameters and ODESSA results is revealed.     

Design and synthesis of new 2‐anilinoquinolines bearing N‐methylpicolinamide moiety as potential antiproliferative agents

A series of new 2‐anilinoquinolines 6a – o possessing the substantial N‐methylpicolinamide motif at C5 has been designed and synthesized as sorafenib analogs. The antiproliferative activities of the target compounds were preliminarily appraised against a panel of three human cancer cell lines (MCF‐7, SK‐BR3, and HCT116), and a selected array was further tested over a panel of approximately 60 cancer cell lines at NCI at 10 μM concentration. Interestingly, compounds 6c , 6d , 6j , 6k , and 6l showed promising selective anticancer activities (growth inhibition >80%) toward certain cancer cells at 10 μM testing dose. Compounds 6d and 6j were advanced to five‐dose testing mode to determine their GI₅₀ values and compared with our previously reported ureidoquinoline B and sorafenib as reference compounds. The 4‐chloro‐3‐trifluoromethylaniline derivative 6j manifested superior potency than both compound B and sorafenib over eleven and eight cell lines, respectively. It showed GI₅₀ values of 0.36, 0.66, 0.68, and 0.60 μM against the breast MDA‐MB‐468, renal A498, and melanoma SK‐MEL‐5 and UACC‐62 cell lines, respectively. Moreover, both 6d and 6j exerted low cytotoxic effects against HFF‐1 normal cell line. Furthermore, compounds 6d and 6j were tested against both B‐Raf^V600E and C‐Raf kinases and displayed modest inhibitory activities, which were justified by molecular docking study. Compound 6j could serve as a promising candidate for further development of potent anticancer chemotherapeutics.