β-Lactam Bioconjugates Bearing Luminescent Platinum(II) Tags: Synthesis and Photophysical...

Job/Unit: O42740 /KAP1 Date: 07-10-14 16:58:14 Pages: 10

FULL PAPER

DOI: 10.1002/ejoc.201402740

β-Lactam Bioconjugates Bearing Luminescent Platinum(II) Tags:Synthesis and Photophysical Characterization

Roberto Soldati,[a] Alessandro Aliprandi,[b] Matteo Mauro,*[b,c] Luisa De Cola,*[b] andDaria Giacomini*[a]

Dedicated to C.I.N.M.P.I.S. on the occasion of its 20th anniversary

Keywords: Bioprobes / Lactams / Theranostic agents / Bioimaging / Platinum / Luminescence

Two novel neutral complexes based on platinum metal ions, atridentate ligand, and a pyridine bearing a β-lactam unit havebeen synthesized and their photophysical properties investi-gated. The complexes show interesting emission propertiesthat, in the solid state, are dominated by the formation of ag-gregates due to the square-planar geometry of the PtII species.

Introduction

β-Lactam compounds are historically well-known as oneof the most important class of antimicrobial agents sincethe discovery of the naturally occurring bicyclic compoundspenicillins and cephalosporins.[1] It was recognized early onthat the four-membered azetidinone ring represents the keypharmacophoric core of β-lactams, as attested to by thediscovery of the monocyclic and potent antibiotic Az-treonam.[2] However, the treatment of bacterial infectionshas been hindered by the increasing emergence of multid-rug-resistant microorganisms, which today represents oneof the greatest challenges in the clinical management of in-fectious diseases.[3] Resistance is an inevitable side effect ofantibiotic use and requires a continuous search for new bac-terial targets and novel therapeutic agents to treat drug-resistant microorganisms.[4] Research in this field remainsactive, and reports of new β-lactam derivatives against re-sistant bacteria continue to appear.[5] In a recent contri-bution from our group, a series of new azetidinones wereevaluated in vitro against Gram-positive and Gram-nega-

[a] Department of Chemistry “G. Ciamician”, University of Bologna,Via Selmi 2, 40126 Bologna, ItalyE-mail: [email protected]://www.unibo.it/docenti/daria.giacomini

[b] ISIS & icFRC, Université de Strasbourg & CNRS,8 rue Gaspard Monge, 67000 Strasbourg, FranceE-mail: [email protected]

[email protected]://decola.u-strasbg.fr/

[c] University of Strasbourg Institute for Advanced Study (USIAS),5 allée du Général Rouvillois, 67083 Strasbourg, FranceSupporting information for this article is available on theWWW under http://dx.doi.org/10.1002/ejoc.201402740.

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Importantly, the formation of closed-shell metal···metal inter-actions in such aggregates leads to new excited states thatconveniently allow excitation in the visible region. The combi-nation of the biologically active azetidinone agent and the in-tense and long-lived emission are of particular interest for de-veloping efficient multifunctional biomedical systems.

tive clinical isolates and, in particular, the new β-lactamswere found to be active against methicillin-resistant andmethicillin-susceptible Staphylococcus Aureus strains,MRSA and MSSA respectively, isolated from patients withcystic fibrosis.[6]

The biological activity of monocyclic β-lactams is notlimited to antibacterial properties, and specific activities arecontinuously emerging with new azetidinone variants. Thedesign and synthesis of new azetidinones thus resulted inthe discovery of valuable inhibitors of serine proteases in-cluding elastase, β-lactamase, phospholipase A2, and bacte-rial signal peptidase, inhibitors of HFAAH, HDAC, Ca-thepsin K, and vasopressin, anticancer, antitubercular, andanti-inflammatory agents.[7]

The study of transition-metal-bioconjugates is an activefield of research that has led to potential therapeutics, andsuch compounds can function as tracers in immunologicalanalysis based on several analytical methods.[8] Further-more, the possibility of combining therapeutic propertieswith diagnostics tools making compounds with dual func-tionality (i.e., theranostic agents) has recently blossomedand allowed such compounds to be simultaneously used aspowerful imaging tools to unveil real-time biochemical pro-cess, compound accumulation, drug activity and interac-tion, and to gather information about the fate of the com-pounds, just to cite a few.[9]

In this respect, much effort is currently devoted to thepreparation of luminescent complexes based on second-and third-row transition metals such as iridium(III), rheni-um(I), ruthenium(II), and platinum(II), for applications inbioimaging in vitro, in cellulo and in vivo.[10] Such increas-


M. Mauro, L. De Cola, D. Giacomini et al.FULL PAPER

Scheme 1. Synthetic procedure for compounds 1 and 2.

ing scientific interest is driven by the fact that judiciouschoice of coordinating ligands together with the presenceof the heavy metal might provide enhanced physicochemicalproperties, such as photostability, large Stokes shifts, tun-able emission colors, and high photoluminescence quantumyield.[10] Furthermore, as a consequence of the formallyspin-forbidden nature of the radiative processes, such tran-sition-metal complexes (TMCs) possess long-lived excitedstates with lifetimes that span over greater orders of magni-tude when compared to widely used organic fluoro-phores[11] (i.e., from nanoseconds to milliseconds and frompicoseconds to nanoseconds for the former and the latter,respectively), allowing the successful employment of time-gated microscopy techniques for imaging purposes.[12] How-ever, TMCs typically show excitation bands in the deep-blue and ultraviolet region, which severely hampers theiruse in real applications for in cellulo and in vivo experi-ments.

Among all the investigated complexes, luminescent plati-num(II) derivatives possess the tendency to aggregate intoself-assembled nanostructures by means of weak π-π andclosed-shell metallophilic (dz2···dz2) interactions.[13] The es-tablishment of such intermolecular interactions leads to theformation of lower-lying excited states, namely metal-metal-to-ligand charge transfer (MMLCT). We have very recentlydemonstrated that it is possible to take advantage of theformation of such aggregates to obtain luminescent TMC-based labels that are able to self-assemble in cellular com-partments, forming highly emitting aggregates as a conse-quence of their protection from quenchers (e.g., dioxygen)in biologically relevant environments.[10a,14] Even moreinterestingly, the formation of MMLCT bands leads to size-able bathochromic shift of both excitation and emission,allowing easy excitation of the probe with visiblelight.[10a,14]

The β-lactams have seldom been studied as ligands formetal complexes,[15] and most of the examples deal withmetallocene derivatives. Recently, examples of Pd and Ptcomplexes with azetidinones[16] and bio-organometallic Irand Rh with β-lactam ligands[17] were reported. However,

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specifically designed metal complex bioconjugates should al-low the possibility to couple the multifaceted biological ac-tivities of β-lactams with photoactive metal complexes. Thiscould represent an interesting combination because amongthe new strategies to combat antibiotic-resistant infections,antimicrobial photodynamic therapy appears promising forthe treatment of local infections caused by both Gram-posi-tive and Gram-negative bacteria.[18,19]

In this paper we propose the first step towards the devel-opment of bioconjugates between azetidinones and lumi-nescent platinum complexes. We have chosen platinum com-pounds because of their interesting photophysics, which canbe tuned upon the formation of aggregates. Furthermore,platinum complexes are widely used in biomedical applica-tions due to their anticancer activity,[20a–20e] and their abil-ity to recognize proteins.[20f–20i] We report on the synthesisand photophysical properties of neutral luminescent plati-num complexes coupled through a coordinated pyridine onthe C4 side chain of the (3R,4R)-3-{(R)-1-[(tert-butyl-dimethylsilyl)oxy]ethyl}azetidin-2-one as a β-lactam model(Scheme 1). The complexes, which bear a trifluoromethyl-substituted tridentate chromophoric ligand, show high ten-dency towards aggregation in biologically relevant environ-ments. Furthermore, it is known in medicinal chemistrythat the presence of the highly hydrophobic trifluoromethylgroups would allow a certain degree of lipophilicity andcellular permeability. Many trifluoromethyl-substituted de-rivatives are indeed known to cross cellular and nuclearmembranes.[21] We can envisage that the molecules reportedand characterized here could therefore be parent com-pounds of a novel set of bioimaging probes with self-as-sembling properties for particular biological targets, such asbacteria, proteins, or receptors.

Results and Discussion

Synthesis

In 1974, Clauss et al. reported that 4-acetoxyazetidin-2-one undergoes a nucleophilic displacement of the acetoxy


β-Lactam Bioconjugates Bearing Luminescent Tags

group with a variety of nucleophiles.[22] This observationprompted many laboratories to use 4-acyloxy-azetidinonesas substrates for the synthesis of a variety of β-lactams andthey are now useful industrial intermediates for the synthe-sis of carbapenem.[23]

Starting from commercially available (3R,4R)-4-acetoxy-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]azetidin-2-one(A, Scheme 1) we took advantage of the aptitude of the 4-acetoxy group to undergo nucleophilic substitution reac-tions and we attempted to insert on the C-4 position of theβ-lactam ring a residue that would act as a suitable metalligand. As a first attempt, 4-OH-pyridine was chosen as anucleophile and the corresponding azetidinone 1 was ob-tained in good yields. On attempting the complexation of 1with PtIICl2(DMSO)2 as the platinum precursor, 2,6-bis[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]pyridine as the tri-dentate ligand (py-CF3-trzH2)[13a,14] in CHCl3, and in thepresence of Hünig base (iPr2EtN) at 50 °C, we obtainedonly the 4-OH-pyridyl-PtII complex 2. A tentative explana-tion is that the C4 position of the expected β-lactam Bcould become activated by the direct conjugation of thephenolic moiety with the pyridine coordinated to platinum.Thus, in the aqueous work-up, displacement of the ligandfrom the azetidinone intermediate B occurred and only pyr-idine complex 2 was isolated (Scheme 1). Compound 2 haspreviously been characterized by De Cola and co-workersand it was not investigated further.[14]

To avoid the electronic coupling between the pyridineand the azetidinone moiety, a short alkyl chain was intro-duced as a spacer. Thus, 3-pyridylpropanol and the 4-acetoxy-azetidinone A were coupled (Scheme 2) to giveazetidinone 3. Compound 3 was then treated with the plati-num(II) precursor and the ligand 2,6-bis[3-(trifluoro-methyl)-1H-1,2,4-triazol-5-yl]pyridine, in the presence of

Scheme 3. Synthetic route to azetidinone-PtII complex 8.

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iPr2EtN in CHCl3 at 50 °C, leading to the β-lactam com-plex 4 (Scheme 2). The new platinum-based bioconjugatewas purified by column chromatography and fully charac-terized.

Scheme 2. Synthetic strategy used to access the new β-lactam plati-num conjugate 4.

However, complex 4 was poorly soluble in organic sol-vents and completely insoluble in water. To improve its sol-ubility, we then inserted a short tetraethylene glycol chainas spacer between the pyridine and the β-lactam moieties.The synthetic pathway is depicted in Scheme 3 and startedfrom the reaction of 4-(chloromethyl)pyridine with tetraeth-ylene glycol to give 5. The new tetraethyleneglycol-pyridylligand 5 was preliminarily evaluated as platinum ligand inreaction with the PtII precursor, obtaining complex 6(Scheme 3) successfully. Treatment of the starting 4-(acet-oxy)azetidinone A with 5 gave the β-lactam complex 7,



Figure 1. Comparison of the 1H NMR (400 MHz) spectra of 3 (bottom), 4 (middle), and 8 (top) in CDCl3.

which was treated with the PtII precursor, the py-CF3-trzH2, and iPr2EtN in CHCl3 at 50 °C to give the desiredβ-lactam complex 8.

The β-lactam conjugate 8 was obtained in 59% yield af-ter flash chromatography purification and fully charac-terized. Complex 8 was very soluble in several organic sol-vents (CH2Cl2, CHCl3, THF, MeOH, ethyl acetate, andacetone), and in water it rapidly formed a colloidal suspen-sion. The purified conjugates 4 and 8 were fully charac-terized by mass spectrometry (ESI), IR, and NMR spec-troscopy. The 1H NMR spectra of compounds 4, 8 and β-lactam 3 are compared in Figure 1. The successful complex-ation of the β-lactam 3 to platinum in compounds 4 and 8was confirmed by the downfield shift of the ortho-aromaticpyridine protons of the C4 side chain of the β-lactam,which moved from 8.5 ppm in compound 3 to 9.4 ppm for4 and 8. In contrast, resonance peaks relative to the peculiarhydrogen atoms on the β-lactam ring b, c, and d (Figure 1)were influenced by complexation to a much lesser extent.Therefore, the β-lactam ring should not be involved in plati-num complexation and it could retain its own characteris-tics and properties. This is an important observation in viewof the possible application of the conjugation describedhere to biologically active azetidinones.


Photophysical Characterization

The complexes 4 and 8 were also fully characterized byusing electronic absorption and steady-state and time-re-solved emission spectroscopy; the corresponding data aresummarized in Table 1. The absorption and emission spec-tra in dilute (concentration 1� 10–5 m) CHCl3 solution atroom temperature and at a concentration of 5� 10–5 m in2-MeTHF glassy matrix at 77 K are displayed in Figure 2.

As shown in the electronic absorption spectrum in diluteCHCl3 fluid solution, both compound 4 and 8 display ab-sorption features in two main regions. At lower energy inthe region 360–400 nm, a weak broad and featureless bandwith molar extinction coefficient, ε, of 0.8 and1.1�103 m–1 cm–1 (at λabs = 403 nm) for compound 4 and8, respectively, is attributable to the overlap of energeticallylower-lying spin-allowed singlet-manifold metal-to-ligandcharge transfer, 1MLCT, and ligand-centered, 1LC, exci-tation processes as typical of similar reported cyclo-metalated platinum(II) complexes.[13a,14,24] Such excitationcan be mainly described as a shift of electron density fromthe filled d metal-based molecular orbitals to the emptyMOs of the tridentate ligand with π* character, dπ(Pt)�π*.On the other hand, the more intense (ε = 0.26–



Table 1. Photophysical data for 4 and 8 in fluid solution at room temperature, 77 K glassy matrix, and solid state.

Room temperature 77 K Solid stateCHCl3 2MeTHF glassy matrix

λabs (ε) λem τ PLQY λem τ (�τ�[b]) λem τ PLQY[nm, (�103 m–1 cm–1)] [nm][a] [ns] (%) [nm][a] [μs] [nm] [ns] [%]

4 255 (22.6), 267 (19.8), 303 464, 492, 278 (77%) 2 451, 480, 4.2, 69% 596 321 55(15.1), 338 (2.6), 402 (0.8) 525, 567 (sh) 13 (23%) 517, 10.7, 31% (6.2)[c]

554 (sh) 3.6, 96%7.7, 4% (3.8)[d]

8 255 (24.4), 266 (22.2), 303 464, 492, 239 (66%) 2 451, 483, 4.0, 71 % 589 341 56(16.4), 338 (3.3), 402 (1.1) 525, 567 (sh) 14 (34%) 517, 571 9.6, 29% (5.6)[c]

3.5, 97%7.7, 3% (3.6)[d]

[a] ‘sh’ denotes shoulder. [b] Amplitude-weighted lifetimes. [c] Recorded at 450 nm. [d] Recorded at 585 nm.

Figure 2. Room temperature (solid traces) absorption and normal-ized emission spectra for samples of compound 4 (black) and 8(red) at 1 �10–5 m in CHCl3 and low temperature (77 K) emissionspectra (dashed traces) at 5 �10–5 m in 2-MeTHF glassy matrix.Emission spectra were collected upon λexc at = 300 nm.

2.44 �104 m–1 cm–1) and structured absorption featurespresent at higher energy (λabs = 250–340 nm) can be attrib-uted to 1LC bands. Unfortunately, the low solubility of thecomplexes in solvents with a wide range of polarity ham-pered studies on solvent dependence. As shown in Figure 2,upon photoexcitation in the range 300–400 nm, dilutedfluid air-equilibrated solutions in CHCl3 of both complexesdisplay moderate (PLQY = 2 %) and structured emission inthe blue region of the visible spectrum with a maximum at464, and vibrational bands at 492, 525, and a shoulder at567 nm. The observed emission band with vibronic pro-gression is similar to other reported platinum(II) derivativesbearing N∧N∧N tridentate chelating motifs and is attrib-uted to π–π* transitions involving the tridentate li-gand.[13a,24d]

All the complexes possess bi-exponential radiative deacti-vation kinetics: τ1 = 278 ns and τ2 = 13 ns for compound 4and τ1 = 239 ns and τ2 = 14 ns for compound 8 (see Table 1for more details). Such bi-exponential de-excitation kineticscan be attributed either to the formation of aggregates, evenin this diluted solution, and therefore the coexistence of dif-ferent species in solution, or to the presence of two close-lying excited states, an emissive state with 3MLCT/3LC na-ture, and an energetically close-lying nonemitting (quench-ing) state.[13a,24d]


To clarify the photophysical behavior, low-temperatureand solid-state measurements have been performed. At77 K in 2-MeTHF glassy matrix (c = 5� 10–5 m), the emis-sion spectra display a slight hypsochromic shift of only621 cm–1 with an enhancement of the band structure, fea-turing maxima at 451, 480, 517 and a shoulder at 554 nmfor compound 4, whereas an additional band is clearly vis-ible for compound 8 at approximately 571 nm. The emis-sion at higher energy (ca. 450 nm) has an amplitude-weighted lifetime of 6.2 and 5.6 μs (for 4 and 8, respec-tively). On the other hand, at longer wavelengths (λem =585 nm), the amplitude-weighted lifetime reduces to 3.8 and3.6 μs, for 4 and 8, respectively. As shown by the excitationspectra at 585 nm for both compounds (see Figure S1 in theSupporting Information), the presence of a lower-energy ex-citation band extending towards 500 nm suggests partial ag-gregation through formation of closed-shell metallophilicPt···Pt interactions. This effect is even stronger for com-pound 8, indicating that the emissive excited state is indeedgenerated by aggregation, with the formation of the lumi-nescent 3MMLCT state. To further support the assignmentof the nature of the emitting excited states, a concentration-dependent emission study was conducted in the range 0.1–5 �10–5 m at low temperature (77 K) for the derivative thatshowed higher tendency toward aggregation, i.e., com-pound 8. The resulting emission and excitation spectra aredisplayed in Figure S2 and S3, respectively, and the corre-sponding lifetimes are listed in Table S1 of the SupportingInformation. As expected from radiative transition attrib-uted to a 3MMLCT emission of the ground state aggregatedplatinum complexes, we observed that, upon increasing theconcentration, both low-energy emission and excitation (re-corded at λem = 585 nm) bands increase their relative inten-sity. On the other hand, the excitation spectra recorded athigher energy (i.e., 450 nm) show a negligible concentrationdependency. Concomitantly, in the time-resolved emissiondecay recorded at 585 nm, the shorter lifetime component(i.e., 4.0 μs) attributed to 3MMLCT increases its relativeweight. A mirrored trend is obtained upon monitoring thelifetime at the higher energy band (λem = 450 nm), for whichthe longer lifetime component (i.e., 10.0 μs) attributed tothe 3LC/3MLCT excited state of the monomeric species in-


M. Mauro, L. De Cola, D. Giacomini et al.FULL PAPERcreases its weight upon dilution. Similar consideration canbe made for complex 4 (see Table 1). Therefore, we can con-clude that at 77 K and even at room temperature in dilutesolution the multiexponential decays are due to the forma-tion of small aggregates. For the latter case, i.e., in diluteCHCl3 solution, we attribute the short component to themonomeric species and to the longer excited-state lifetimeto the aggregates.

The assembling formation for the β-lactam-platinumconjugates 4 and 8 have also been investigated in the solidstate, and the corresponding normalized excitation andemission spectra are reported in Figure 3. Interestingly,upon photoexcitation between 300 and 400 nm, the solid-state samples display a very intense emission band centeredat 596 and 589 nm with PLQY as high as 55 and 56 % forcompound 4 and 8, respectively. The excited-state lifetimesdecay with monoexponential kinetics and are 321 and341 ns for complex 4 and 8, respectively. Similar to the 77 Kspectra, such bright emission is attributable to the3MMLCT emitting excited-state established upon aggrega-tion of the complex in the solid state. Even more interest-ingly, the excitation spectra recorded at the maximum ofemission wavelength display a typical 1MMLCT band withonset wavelength as long as 580 nm for compound 4, al-lowing the possibility to excite such luminescent probes intheir aggregated form with visible light with a wavelengththat approaches the so-called therapeutic window (600–1300 nm).

Figure 3. Normalized excitation (dotted traces) and emission (solidtraces) spectra for solid-state samples of 4 (black) and 8 (red). Exci-tation and emission spectra were collected at the λem maximum andupon λexc at 350 nm, respectively.

Overall, the several nanosecond lifetime scale, the verybright emission in air-equilibrated conditions of the aggre-gated compounds, as well as the excellent stability of thecompounds, are valuable properties that should facilitatefurther exploration of the behavior of such species forbioapplications and as theranostic agents.

Conclusions

New complexes based on platinum metal ions, a tridentate dianionic ligand (upon deprotonation of the tri-azole moieties), and a pyridine bearing a β-lactam unit were


successfully synthesized and the new β-lactam platinumconjugates showed interesting photophysical properties.Furthermore, the formation of aggregates, due to thesquare-planar geometry of the PtII species, leads to new ex-cited states that allow excitation in the visible region. Thecombination of a biologically active agent (the β-lactamunit) and an intense and long-lived emission (platinumcomplex) are of particular interest for the development ofbiomedical systems in which imaging and antimicrobialproperties are combined in a single compound.

Experimental SectionGeneral: Commercial reagents were used as received without ad-ditional purification. 1H, 13C, and 19F NMR spectra were recordedwith an INOVA 400 or a Bruker Avance 400 instrument with a5 mm probe. All chemical shifts are quoted relative to deuteratedsolvent signals (δ in ppm and J in Hz). TLC was performed withMerck 60 F254 plates. Column chromatography was performed withMerck silica gel 200–300 mesh. HPLC-MS were recorded with anAgilent Technologies HP1100 instrument, equipped with a ZOB-RAX-Eclipse XDB-C8 Agilent Technologies column (mobilephase: H2O/CH3CN, 0.4 mL/min, gradient from 30 to 80%CH3CN in 8 min, 80% CH3CN until 25 min), coupled with an Ag-ilent Technologies MSD1100 single-quadrupole mass spectrometer,full scan mode from m/z 50 to 2600, scan time 0.1 s in positive ionmode, ESI spray voltage 4500 V, nitrogen gas 35 psi, drying gasflow 11.5 mL/min, fragmentor voltage 20 V. Elemental analysiswere performed with a Thermo Flash 2000 CHNS/O Analyzer.

(3R,4R)-3-{(R)-1-[(tert-Butyldimethylsilyl)oxy]ethyl}-4-(pyridin-4-yloxy)azetidin-2-one (1): In a 25 mL flask, to a stirred solution ofA (143 mg, 0.5 mmol) in acetonitrile (1.0 mL) were slowly addedH2O (4.0 mL), then 4-hydroxypyridine (95 mg, 1.0 mmol) and fi-nally Et3N (154 μL, 1.1 mmol). The reaction was followed by TLC(EtOAc/cyclohexane, 8:2) and after 1 h stirring, the mixture wasextracted with CH2Cl2 (3� 10 mL), dried with Na2SO4, and evapo-rated in vacuo. After flash-chromatography purification (acetoneto acetone/MeOH, 95:5), the desired product 1 (144 mg, 100%) wasobtained as a white solid; [α]D = 29.8 (c = 0.62, CH2Cl2). 1H NMR(400 MHz, CDCl3): δ = 0.10 (s, 3 H, MeSi), 0.12 (s, 3 H, MeSi),0.89 (s, 9 H, tBuSi), 1.25 (d, J = 7.4 Hz, 3 H, Me), 3.20 (dd, J =1.5, 4.2 Hz, 1 H, CHCONH), 4.28 (m, 1 H, CHOTBS), 5.43 (s, 1H, CHOPyr), 6.37 (d, J = 7.6 Hz, 2 H, ArH), 7.55 (d, J = 7.6 Hz,2 H, ArH), 7.88 (s, 1 H, NH) ppm. 13C NMR (100.6 MHz, CDCl3):δ = –5.0, –4.3, 17.9, 22.5, 25.7, 64.4, 68.1, 68.5, 118.9, 136.3, 165.7,179.6 ppm. IR (neat): ν̃ = 3391, 2956, 2929, 2857, 1784, 1634, 1549,1386, 1257, 1174, 1099, 982, 836, 776 cm–1. HPLC-MS (ESI+): Rt

= 6.70 min; m/z = 323 (100) [M + H]+, 645 (59) [2M + H]+, 667(23) [2M + Na]+.

{2,6-Bis[3-(trifluoromethyl)-1,2,4-triazol-5-yl]pyridine}PtII[pyridin-4-ol] (2): Compound 2 is a known compound,[14] and was preparedas follows. In a 25 mL two-neck flask with a Liebig condensor un-der a nitrogen atmosphere, to a stirred solution of 1 (84 mg,0.23 mmol) in chloroform (10.0 mL) were added 2,6-bis[3-(tri-fluoromethyl)-1H-1,2,4-triazol-5-yl]pyridine (80 mg, 0.23 mmol),PtCl2(DMSO)2 (97 mg, 0.23 mmol), and N-ethyl-N,N-diisopropyl-amine (80 μL, 0.46 mmol). The mixture was heated at 50 °C, stirredovernight and then analyzed by TLC (EtOAc/acetone, 8:2). Directevaporation afforded a crude reaction mixture that was purifiedby flash-chromatography (EtOAc/acetone, 9:1 to acetone) to givecomplex 2 (102 mg, 70%) as a yellow luminescent waxy solid.



(3R,4R)-3-{(R)-1-[(tert-Butyldimethylsilyl)oxy]ethyl}-4-[3-(pyridin-4-yl)propoxy]azetidin-2-one (3): In a 25 mL two-neck flask driedand under a nitrogen atmosphere, to a stirred solution of A(143 mg, 0.5 mmol) in dioxane (5.0 mL), 3-pyridine-propanol(274 mg, 2.0 mmol) and ZnBr2 (450 mg, 2.0 mmol) were added.The reaction was monitored by TLC (EtOAc/cyclohexane, 8:2) andafter 56 h it was quenched by stirring with saturated aqueousNaHCO3 (5 mL), extracted with CH2Cl2 (3� 10 mL), dried withNa2SO4, and evaporated in vacuo. After flash-chromatography pu-rification (EtOAc/cyclohexane, 4:6 to 8:2), compound 3 (111 mg,61 %) was obtained as a colorless oil. [α]D = –1.9 (c = 0.76,CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 0.06 (s, 3 H, MeSi),0.08 (s, 3 H, MeSi), 0.87 (s, 9 H, tBuSi), 1.25 (d, J = 6.2 Hz, 3 H,Me), 1.94 (m, 2 H, OCH2CH2) , 2.71 (t , J = 7.6 Hz, 2 H,OCH2CH2CH2), 3.02 (d, J = 4.2 Hz, 1 H, CHCONH), 3.49 (t, J= 6.4 Hz, 2 H, OCH2), 4.17 (m, 1 H, CHOTBS), 5.04 (s, 1 H,CHNH), 6.61 (br. s, 1 H, NH), 7.12 (d, J = 4.0 Hz, 2 H, ArH), 8.50(d, J = 4.0 Hz, 2 H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3): δ= –5.1, –4.4, 17.9, 22.5, 25.7, 29.9, 31.5, 64.2, 65.5, 66.6, 80.5,124.0, 149.3, 150.9, 167.9 ppm. IR: ν̃ = 3227, 2955, 2929, 2857,1767, 1605, 1463, 1417, 1361, 1255, 1120, 1098, 836 cm–1. HPLC-MS (ESI+): Rt = 9.65 min; m/z = 365 [M + H]+.

{2,6-Bis[3-(trifluoromethyl)-1,2,4-triazol-5-yl]pyridine}PtII((3R,4R)-3-{(R)-1-[(tert-butyldimethylsilyl)oxy]ethyl}-4-[3-(pyridin-4-yl)prop-oxy]azetidin-2-one) (4): In a 25 mL two-neck flask with a Liebigcondensor under nitrogen atmosphere, to a stirred solution of 3(60 mg, 0.165 mmol) in chloroform (7.2 mL), 2,6-bis[3-(trifluoro-methyl)-1H-1,2,4-triazol-5-yl]pyridine (58 mg, 0.165 mmol),PtCl2·(DMSO)2 (67 mg, 0.165 mmol) and N-ethyl-N,N-diisopropyl-amine (69 μL, 0.396 mmol) were added. The mixture was heated at50 °C overnight and analyzed by TLC (EtOAc). Direct evaporationof the reaction solvent afforded a crude product that was purifiedby flash-chromatography (CH2Cl2/EtOAc, 3:7), to obtain 4 (58 mg,39%) as a yellow to orange fluorescent waxy solid. [α]D = –2.8 (c= 0.87, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 0.07 (s, 3 H,MeSi), 0.09 (s, 3 H, MeSi), 0.87 (s, 9 H, tBuSi), 1.29 (d, J = 6.4 Hz,3 H, Me), 2.03–2.12 (m, 2 H, OCH2CH2), 2.75–2.99 (m, 2 H,OCH2CH2CH2), 3.06 (d, J = 3.6 Hz, 1 H, CHCONH), 3.50–3.55(m, 1 H, OCHAHB), 3.56–3.66 (m, 1 H, OCHAHB), 4.12–4.26 (m,1 H, CHOTBS), 5.09 (s, 1 H, CHNH), 6.94 (s, 1 H, NH), 7.34 (d,J = 6.2 Hz, 2 H, ArH), 7.63 (d, J = 8.0 Hz, 2 H, ArH), 7.90 (t, J= 8.0 Hz, 1 H, ArH), 9.33 (d, J = 6.2 Hz, 2 H, ArH) ppm. 13CNMR (100.6 MHz, CDCl3): δ = –5.1, –4.3, 17.9, 22.5, 25.7, 28.9,31.7, 64.3, 65.6, 66.0, 80.5, 118.1, 119.6 (q, 1JC–F = 270 Hz), 121.0,126.4, 143.0, 148.4, 152.5, 152.6 (q, 2JC–F = 38 Hz), 155.4, 163.5,167.8 ppm. 19F NMR (400 MHz, CDCl3): δ = –64.1 ppm. IR: ν̃ =3286, 2958, 2930, 2858, 1767, 1628, 1482, 1202, 1156, 1132,1098 cm–1. MS (ESI+): m/z = 907 [M + H]+, 929 [M + Na]+, 1836[2M + Na]+. C30H35F6N9O3PtSi (906.83): calcd. C 39.73, H 3.89,N 13.90; found C 39.65, H 4.21, N 12.44.

1-(Pyridin-4-yl)-2,5,8,11-tetraoxatridecan-13-ol (5): In a 100 mLtwo-neck flask under a nitrogen atmosphere, to a stirred solutionof 4-chloromethyl-pyridine hydrochloride (820 mg, 5.0 mmol) inacetonitrile (40.0 mL) were added tetraethylene glycol (949 μL,6.5 mmol) and Et3N (1.4 mL, 10.0 mmol). After 1 h stirring, NaH(60% in oil, 400 mg, 10.0 mmol) was added and the mixture wasstirred overnight at room temperature. The progress of the reactionwas monitored by TLC (EtOAc/cyclohexane, 8:2) and the reactionmixture was concentrated under vacuum. The obtained crude prod-uct was then purified by flash-chromatography (acetone/MeOH,95:5) to obtain alcohol 5 (217 mg, 76%) as a colorless oil. 1H NMR(400 MHz, CDCl3): δ = 3.60–3.73 (m, 16 H, OCH2CH2O), 4.61 (s,2 H, OCH2Ar), 7.36 (d, J = 5.2 Hz, 2 H, ArH), 8.60 (d, J = 5.2 Hz,


2 H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 60.8, 69.5,69.6, 69.7, 69.9, 70.0, 70.8, 72.2, 72.3, 121.3, 147.4, 148.9 ppm. IR:ν̃ = 3375, 2969, 2925, 2879, 1465, 1419, 1378, 1301, 1127, 1106,952 cm–1. HPLC-MS (ESI+): Rt = 1.28 min; m/z = 286 [M + H]+.

{2,6-Bis[3-(trifluoromethyl)-1,2,4-triazol-5-yl]pyridine}PtII[1-(pyr-idin-4-yl)-2,5,8,11-tetraoxatridecan-13-ol] (6): In a 25 mL two-neckflask equipped with a Liebig condensor under a nitrogen atmo-sphere, to a stirred solution of 5 (48 mg, 0.17 mmol) in chloroform(7.4 mL), 2,6-bis[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]pyridine(59 mg, 0.17 mmol), PtCl2·(DMSO)2 (72 mg, 0.17 mmol) and N-ethyl-N,N-diisopropylamine (71 μL, 0.408 mmol) were added. Themixture was heated at 50 °C, stirred overnight and then analyzedby TLC (acetone/EtOAc, 8:2). Direct solvent evaporation of thereaction mixture afforded a crude product that was purified byCombiFlash (CH2Cl2/MeOH, 98:2) to obtain 6 (45 mg, 32 %) as ayellow to orange fluorescent waxy solid. 1H NMR (400 MHz,CDCl3): δ = 3.56–3.87 (m, 16 H, OCH2CH2O), 4.76 (s, 2 H,OCH2Ar), 7.68 (d, J = 6.0 Hz, 2 H, ArH), 7.89 (d, J = 8.0 Hz, 2H, ArH), 8.08 (t, J = 8.0 Hz, 1 H, ArH), 9.62 (d, J = 6.0 Hz, 2 H,ArH) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 61.6, 70.3, 70.4,70.5, 70.6, 70.6, 70.7, 70.7, 72.5, 117.8, 119.4 (q, 1JC–F = 269 Hz),123.5, 142.7, 147.7, 152.0, 152.1 (q, 2JC–F = 38 Hz), 152.6,163.0 ppm. 19F NMR (400 MHz, CDCl3): δ = –64.3 ppm. IR: ν̃ =3423, 3062, 2922, 2363, 1629, 1482, 1463, 1132 cm–1. MS (ESI+):m/z = 850 [M + Na]+, 1677 [2M + Na]+. C25H26F6N8O5Pt (827.61):calcd. C 36.28, H 3.17, N 13.54; found C 35.99, H 3.52, N 11.90.

(3R,4R)-3-{(R)-1-[(tert-Butyldimethylsilyl)oxy]ethyl}-4-{[1-(pyridin-4-yl)-2,5,8,11-tetraoxatridecan-13-yl]oxy}azetidin-2-one (7): In a25 mL two-necked flask equipped with a Liebig condensor, driedand under a nitrogen atmosphere, to a stirred solution of A(143 mg, 0.5 mmol) in dioxane (4.0 mL), 5 (142 mg, 0.5 mmol) andZnBr2 (112 mg, 0.5 mmol) were added. The reaction was warmedto 50 °C and monitored by TLC (EtOAc). After 30 h stirring, thereaction was quenched with saturated aqueous NaHCO3 (5 mL)and the solvents were evaporated under vacuum. The solid mixturewas treated with a mixture of MeCN/MeOH (1:1, 10 mL), filtered,and the liquid phase was concentrated under vacuum. After flash-chromatography purification (EtOAc to EtOAc/MeOH, 95:5),product 7 (90 mg, 35%) was obtained as a colorless oil. [α]D = 4.4(c = 1.00, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 0.06 (s, 3 H,MeSi), 0.07 (s, 3 H, MeSi), 0.88 (s, 9 H, tBuSi), 1.25 (d, J = 6.4 Hz,3 H, Me), 2.94 (dd, J = 1.2, 4.0 Hz, 1 H, CHCONH), 3.44–3.96(m, 16 H, OCH2CH2O), 4.11–4.18 (m, 1 H, CHOTBS), 4.60 (s, 2 H,OCH2Ar), 5.00 (d, J = 1.2 Hz, 1 H, CHNH), 7.29 (d, J = 5.6 Hz, 2H, ArH), 7.51 (s, 1 H, NH), 8.57 (d, J = 5.6 Hz, 2 H, ArH) ppm.13C NMR (50.3 MHz, CDCl3): δ = –5.1, –4.2, 17.9, 22.4, 25.7, 26.5,64.5, 65.4, 69.9, 70.2, 70.3, 70.4, 70.5, 70.7, 71.2, 71.5, 82.8, 122.2,148.1, 149.9, 167.6 ppm. IR: ν̃ = 3330, 2955, 2928, 2858, 1764,1462, 1375, 1253, 1103, 949, 778, 732 cm–1. HPLC-MS (ESI+): Rt

= 1.45 min; m/z = 513 [M + H]+.

{2,6-Bis[3-(trifluoromethyl)-1,2,4-triazol-5-yl]pyridine}PtII((3R,4R)-3-{(R)-1-[(tert-butyldimethylsilyl)oxy]ethyl}-4-{[1-(pyridin-4-yl)-2,5,8,11-tetraoxatridecan-13-yl]oxy}azetidin-2-one) (8): In a 25 mLtwo-neck flask with a Liebig condensor under a nitrogen atmo-sphere, to a stirred solution of 7 (44 mg, 0.086 mmol) in chloroform(7.2 mL), 2,6-bis[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]pyridine(30 mg, 0.086 mmol), PtCl2·(DMSO)2 (36 mg, 0.086 mmol) and N-ethyl-N,N-diisopropylamine (36 μL, 0.206 mmol) were added. Themixture was heated at 50 °C overnight and then analyzed by TLC(EtOAc/acetone, 8:2). Evaporation of the reaction solvent affordeda crude product that was purified by flash-chromatography(EtOAc/acetone, 95:5) to obtained 8 (54 mg, 59%) as a yellow to


M. Mauro, L. De Cola, D. Giacomini et al.FULL PAPERorange luminescent waxy solid. [α]D = –0.4 (c = 0.91, THF). 1HNMR (400 MHz, CDCl3): δ = –0.01 ppm (s, 3 H, MeSi), 0.00 (s, 3H, MeSi), 0.80 (s, 9 H, tBuSi), 1.17 (d, J = 6.4 Hz, 3 H, Me), 2.88(d, J = 4.4 Hz, 1 H, CHCONH), 3.46–3.85 (m, 16 H, OCH2CH2O),4.02–4.14 (m, 1 H, CHOTBS), 4.68 (s, 2 H, OCH2Ar), 4.91 (s, 1H, CHNH), 7.46 (s, 1 H, NH), 7.53 (d, J = 6.0 Hz, 2 H, ArH),7.72 (d, J = 8.0 Hz, 2 H, ArH), 7.95 (t, J = 8.0 Hz, 1 H, ArH), 9.48(d, J = 6.0 Hz, 2 H, ArH) ppm. 13C NMR (50.3 MHz, CDCl3): δ= –3.7, –3.6, 14.0, 22.6, 23.8, 25.6, 61.7, 66.3, 66.9, 67.4, 67.6, 70.4,70.7, 70.8, 72.5, 82.5, 118.0, 120.8 (q, 1JC–F = 265 Hz), 123.7, 142.9,148.4, 152.6, 152.7 (q, 2JC–F = 40 Hz), 152.8, 160.9, 163.5 ppm. 19FNMR (400 MHz, CDCl3): δ = –64.2 ppm. MS (ESI+): m/z = 1077[M + Na]+. C36H47F6N9O7PtSi (1054.99): calcd. C 40.99, H 4.49,N 11.95; found C 40.88, H 4.20, N 12.30.

Photophysical Investigation: Absorption spectra were measuredwith a Shimadzu UV-3600 double-beam UV/Vis/NIR spectropho-tometer and baseline corrected. For both room temperature fluidsolution in CHCl3 and 2-MeTHF glassy matrix samples at 77 K,steady-state emission spectra were recorded with a HORIBAJobin–Yvon IBH FL-322 Fluorolog 3 spectrometer equipped witha 450 W Xenon arc lamp, double grating excitation and emissionmonochromators (2.1 nm mm–1; 1200 grooves mm–1) and R2568Pdetector. Emission and excitation spectra were corrected for sourceintensity (lamp and grating) and emission spectral response (detec-tor and grating) by standard correction curves. Time-resolved mea-surements were performed by using either time-correlated single-photon counting (TCSPC) electronics PicoHarp300 or the MultiChannel Scaling (MCS) electronics NanoHarp 250 of the PicoQu-ant FluoTime 300 (PicoQuant GmbH, Germany), equipped with aPDL 820 laser pulse driver. A pulsed laser diode LDH-P-C-375 (λ= 375 nm, pulse FWHM � 70 ps, repetition rate 200 kHz to40 MHz) was used to excite the sample and mounted directly onthe sample chamber at 90°. The photons were collected with aPMA-C-192 photomultiplier (PMT) single-photon-counting detec-tor. The data were acquired by using the commercially availablesoftware EasyTau (PicoQuant GmbH, Germany), and data analy-sis was performed by using the commercially available softwareFluoFit (PicoQuant GmbH, Germany). The goodness-of-fit wasassessed by minimizing the reduced chi-square function (χ2) andvisual inspection of the weighted residuals. For multiexponentialdecays, the intensity, namely I(t), was assumed to decay as the sumof individual single exponential decays as shown below; τ1 are thedecay times and ai are the amplitude of the component at t = 0.

The percentages to the pre-exponential factors, ai, are listed uponnormalization. The quantum yield measurements were performedby using an absolute photoluminescence quantum yield spectrome-ter Quantaurus C11347 (Hamamatsu, Japan) exciting the sampleat λexc = 350 nm. All the solvents used for the photophysical mea-surements were of spectroscopic grade.

Supporting Information (see footnote on the first page of this arti-cle): Copies of the 1H, 19F, and 13C NMR spectra of compounds 1and 3–8, and Figure S1–S3 of additional spectra recorded at 77 Kfor compounds 4 and 8.

Acknowledgments

L. D. C., M. M., and A. A. kindly acknowledge the University ofStrasbourg, Centre National de la Recherche Scientifique (CNRS),


the LabEx “Chemistry of Complex Systems”, and the Ministère del’Enseignement Supérieur de la Recherche (MESR), the Inter-national Center for Frontier Research in Chemistry (icFRC).L. D. C. is grateful to the Région Alsace and the Communauté Ur-baine de Strasbourg for the award of a Gutenberg Excellence Chair(2011–2012) and to AXA Research funds. D. G. and P. G. greatlythank the Italian Cystic Fibrosis Research Foundation, projectnumber FFC#9/2013 (adopted by the Gruppo di Sostegno FFCdi Seregno, Delegazione FFC di Cecina, Delegazione FFC dellaValpolicella) and the Ministero dell’Istruzione dell’Università edella Ricerca (MIUR, PRIN project). Prof. Paola Galletti isthanked for fruitful discussions and elemental analysis. R. S. thanksthe University of Bologna for a PhD grant (Marco Polo PhD stud-ents exchange program).

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Received: June 11, 2014Published Online: �



Bioconjugate β-Lactams

New complexes based on a β-lactam unit R. Soldati, A. Aliprandi, M. Mauro,*and platinum metal ion were synthe- L. De Cola,* D. Giacomini* ............ 1–10sized and the β-lactam conjugatesshowed interesting photophysical proper- β-Lactam Bioconjugates Bearing Lumi-ties. The formation of aggregates, due to nescent Platinum(II) Tags: Synthesis andthe square-planar geometry of the PtII Photophysical Characterizationspecies, leads to new excited states that al-low excitation in the visible region. Keywords: Bioprobes / Lactams / Theranos-

tic agents / Bioimaging / Platinum / Lumi-nescence


β-Lactam Bioconjugates Bearing Luminescent Platinum(II) Tags: Synthesis and Photophysical...

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