Photoacoustic (PA) imaging shows promise in the sensitive detection of caspase-3 activated in early tumor apoptosis in response to chemotherapy; smart PA probes are thus in high demand. Herein, we report the first smart PA probe (1-RGD)r esponsive to caspase-3, enabling real-time and high-resolution imaging of tumor apoptosis. 1-RGD is designed to leverage the synergetic effect of active delivery and caspase-3 activation. It is selectively recognized by active caspase-3 to trigger peptide substrate cleavage and biocompatible macrocyclization-mediated self-assembly,leading to an amplified PA imaging signal and prolonged retention in apoptotic tumor cells.S trong,h igh-resolution PA images are obtained in chemotherapy-induced apoptotic tumors in living mice after intravenous administration with 1-RGD,facilitating sensitive reporting of caspase-3 activity and distribution within tumor tissues.Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.

Renal-clearable and target-responsive near-infrared (NIR) fluorescent imaging probes have been promising for in vivo diagnosis of acute kidney injury (AKI). However, designing an imaging probe that is renal-clearable and concurrently responsive toward multiple molecular targets to facilitate early detection of AKI with improved sensitivity and specificity is challenging. Herein, by leveraging the receptor-mediated binding and retention effect along with enzyme-triggered fluorescence activation, we design and synthesize an activatable small-molecule NIR fluorescent probe (1-DPA 2 ) using a “one-pot sequential click reaction” approach. 1-DPA 2 can target both the externalized phosphatidylserine (PS) and active caspase-3 (Casp-3), two essential biomarkers of apoptosis, producing enhanced 808 nm NIR fluorescence and a high signal-to-background ratio (SBR) amenable to detecting the onset of cisplatin-induced AKI in mice as early as 24 h post-treatment with cisplatin. We not only monitor the gradual activation of Casp-3 in the kidney of mice upon AKI progression but also can report on the progressive recovery of kidney functions in AKI mice following N-acetyl-l-cysteine (NAC) therapy via real-time fluorescence imaging by 1-DPA 2 . This study demonstrates the ability of 1-DPA 2 for longitudinal monitoring of renal cell apoptosis by concurrently targeting PS externalization and Casp-3 activation, which is efficient for early diagnosis of AKI and useful for prediction of potential drug nephrotoxicity as well as in vivo screening of anti-AKI drugs’ efficacy.

Full details of studies leading to the total synthesis of the teicoplanin aglycon are provided. Key elements of the first generation approach (26 steps from constituent amino acids, 1% overall) include the coupling of an EFG tripeptide precursor to the common vancomycin/teicoplanin ABCD ring system and sequential DE macrocyclization of the 16-membered ring with formation of the diaryl ether via a phenoxide nucleophilic aromatic substitution of an o-fluoronitroaromatic (80%, 3:1 atropisomer diastereoselection) followed by 14-membered FG ring closure by macrolactamization (66%). Subsequent studies have provided a second generation total synthesis which is shorter, more convergent, and highly diastereoselective (22 steps, 2% overall). This was accomplished by altering the order of ring closures such that FG macrolactamization (95%) preceded coupling of the EFG tripeptide to the ABCD ring system and subsequent DE ring closure. Notably, DE macrocyclization via diaryl ether formation on substrate 57, the key intermediate in the latter approach incorporating the intact FG ring system, occurred with exceptional diastereoselection for formation of the natural atropisomer (>10:1, 76%) without problematic C(2)(3) epimerization provided the basicity of the reaction is minimized.

Teicoplanin 1,2 is a complex of five antibiotics isolated from Actinoplanes teichomyceticus that are related to vancomycin [3][4][5][6][7][8] which is enlisted as the drug of last resort for treatment of resistant bacterial infections or for patients allergic to -lactam antibiotics. 6 It is 2-8-fold more potent, possesses a lower toxicity, exhibits a longer half-life in man (40 vs 6 h), and is easier to administer and monitor than vancomycin.Herein we describe the first total synthesis of the teicoplanin aglycon (1). 9-12 Although teicoplanin bears the identical ABCD ring system and the same CDE atropisomer stereochemistry as vancomycin, it contains a DE ring system that lacks the -hydroxy group of the vancomycin E-ring substituted phenylalanine (C 2 residue) and incorporates an especially racemization prone substituted phenylglycine C 3 residue. 13 Most significantly, it contains the additional 14-membered FG ring system not found in vancomycin. Key elements of the approach include sequential DE and FG ring system introductions onto the common vancomycin/teicoplanin ABCD ring system providing a late stage divergent total synthesis of the two classes of glycopeptide antibiotics. The ring systems were introduced enlisting a nucleophilic aromatic substitution reaction of an o-fluoronitroaromatic for macrocyclization and formation of the 16-membered DE diaryl ether and a macrolactamization 14 of the N-terminus amide for closure of the 14-membered FG ring system. With the respective order of closures, the choice of substrates, and the conditions enlisted, no epimerization of the sensitive C 2 3 center was observed.Because of the facile C 2 3 epimerization observed within the confines of the teicoplanin FG ring system, 13 the FG diaryl ether was formed using an intermolecular nucleophilic aromatic substitution reaction with acyclic phenylglycinol substrates incapable of epimerization. Thus, coupling of 2 15 and 3 16 (6 equiv of K 2 CO 3 , 5 equiv of 18-c-6, 0.1 M DMSO, 14 h, 25°C) provided 4 (70%), Scheme 1. Reactions conducted in DMSO were substantially faster than those conducted in DMF and the (1) Parenti, F.; Beretta, G.; Berti, M.; Arioli, V. J. Antibiot. 1978, 31, 276. (2) Hunt, A. H.; Molloy, R. M.; Occolowitz, J. L.; Marconi, G. G.; Debono, M. J. Am. Chem. Soc. 1984, 106, 4891. Barna, J. C. J.; Williams, D. H.; Stone, D. J. M.; Leung, T.-W. C.; Doddrell, D. M. J. Am. Chem. Soc. 1984, 106, 4895. (3) McCormick, M. H.; Stark, W. M.; Pittenger, G. E.; Pittenger, R. C.; McGuire, J. M. Antibiot. Annu. 1955-1956, 606. (4) Harris, C. M.; Kopecka, H.; Harris, T. M. J. Am. Chem. Soc. 1983, 105, 6915. Williamson, M. P.; Williams, D. H. (10) Nicolaou, K. C.; Li, H.; Boddy, C. N. C.; Ramanjulu, J. M.; Yue, T.-Y.; Natarajan, S.; Chu, X.-J.; Bräse, S.; Rübsam, F. Chem. Eur. J. 1999, 5, 2584. Nicolaou, K. C.; Boddy, C. N. C.; Li, H.; Koumbis, A. E.; Hughes, R.; Natarajan, S.; Jain, N. F.; Ramanjulu, J. M.; Bräse, S.; Solomon, M. E. Chem. Eur. J. 1999, 5, 2602. Nicolaou, K. C.; Koumbis, A. E.; Takayanagi, M.; Natarajan, S.; Ja...

Stimuli-responsive in situ self-assembly of small molecule probes into nanostructures has been promising for the construction of molecular probes for in vivo imaging.