For centuries, Bombyx mori silkworm silk fibroin has been used as a high-end textile fiber. Beyond textiles, silk fibroin has also been used as a surgical suture material for decades, and is being ...further developed for various emerging biomedical applications. The facile and versatile processability of silk fibroin in native and regenerated forms makes it appealing in a range of applications that require a mechanically superior, biocompatible, biodegradable, and functionalizable material. In this review, we describe the current understandings of the constituents, structures, and mechanical properties of silk fibroin. Following that, we summarize the strategies to bring its mechanical performance closer to that of spider dragline silk. Next, we discuss how functionalization endows silk fibroin with desired functionalities and also the effects of functionalization on its mechanical properties. Finally, from the mechanical point of view, we discuss various matrices/morphologies of silk fibroin, and their respective applications in term of functionalities, mechanical properties and performance.
The site selectivity for lysine conjugation on a native protein is difficult to control and characterize. Here, we applied mass spectrometry to examine the conjugation kinetics of Trastuzumab-IgG ...(Her-IgG) and α-lactalbumin under excess linker concentration (L
) based on the modified Michaelis-Menten equation, in which the initial rate constant per amine (k
= V
/K
) was determined by the maximum reaction rate (V
) under saturated accessible sites and initial amine-linker affinity (1/K
). Reductive amination (RA) displayed 3-4 times greater V
and a different panel of conjugation sites than that observed for N-hydroxysuccinimide ester (NHS) chemistry using the same length of polyethylene glycol (PEG) linkers. Moreover, faster conversion power rendered RA site selectivity among accessible amine groups and a greater tunable range of linker/protein ratio for aldehyde-linkers compared to those of the same length of NHS-linkers. Single conjugation with high yield or poly-conjugations with site homogeneity was demonstrated by controlling L
or gradual addition to minimize the L
/K
ratio. Formaldehyde, the shortest aldehyde-linker with the greatest 1/K
, exhibited the highest selectivity and was shown to be a suitable probe to predict conjugation profile of aldehyde-linkers. Four linkers on the few probe-predicted hot spots were elucidated by kinetically controlled RA with conserved drug efficacy when conjugated with the payload. This study provides insights into controlling factors for homogenous and predictable amine bioconjugation.
In this work, copper (Cu) species were used as reducing reagents in the colloidal preparation of novel cross-shaped gold (Au) nanostructures in oleylamine. The reduction rate can be controlled ...through an appropriate choice of Cu species to obtain Au nanocrosses of varying sizes. It was found that the presence of Cu species during the nucleation stage is crucial to the formation of a branched morphology. Further analysis revealed that the four primary branches of the Au nanocrosses grow along the and directions, and that secondary branched growth occurs along the direction. First-principles calculations and phase-field models were used to rationalize the observed preferential branching and understand the morphological evolution of the nanocrosses. These unique cross-like Au nanostructures exhibit strong NIR absorption and remarkable plasmonic properties that make them promising materials for optical and biomedical applications.
In this study, we reported the inhibition profiles of 4′‐acylpyrrole–5‐fluoroindolin‐2‐one 3 with a C‐3′ side chain for VEGFR2, PDGFR‐β, and FGFR‐1 protein kinases. The pyrrole‐fused cyclohexanone ...moiety provided 3 with the best potency to inhibit the three kinases, and the C‐3′ side chains contributed to the different inhibition profiles of 3. Compound 3b with a C‐3′ 2‐carboxylethyl side chain showed good potency for the three kinase (IC50: 25–260 nM), and compound 3g with a N,N‐dialkyl‐2‐carbamoylethyl side chain was more active for VEGFR2 (IC50: 59 nM) and PDGFR‐β (IC50: 16 nM) than FGFR‐1 (IC50: 1.7 μM). The C‐3′ 3‐(dialkylamino)propyl side chain accomplished 3h–j as selective PDGFR‐β inhibitors (IC50: 7.8–13 nM). Compound 3b was further investigated and found potent to inhibit VEGF‐ and FGF‐dependent cell proliferation with moderate in vivo anticancer activity. Results from docking simulations revealed that the interactions of 3b with VEGFR2 and FGFR‐1 which could account for the different inhibition profiles of 3.
4'‐Acylpyrrole–5‐fluoroindolin‐2‐ones with a C‐3′ side chain showed different inhibition profiles for VEGFR2, PDGFR‐β, and FGFR‐1 protein kinases. Representative compound 3b was potent for the three kinases, whereas 3g and 3h were selective VEGFR2/PDGFR‐β and selective PDGFR‐β inhibitors, respectively.
According to the 2005 World Health Organization classification of head and neck tumors, neuroendocrine tumors can be subdivided into typical carcinoid, atypical carcinoid, and small cell carcinoma. ...Similar tumors diagnosed as large cell neuroendocrine carcinomas (LCNECs) in the lung are diagnosed as atypical carcinoids in the head and neck region. We studied neuroendocrine tumors and analyzed whether LCNEC should be separated from atypical carcinoid in the head and neck region. Twenty-three cases of primary head and neck neuroendocrine tumors were included and subdivided into typical carcinoid, atypical carcinoid, and small cell carcinoma according to the 2005 World Health Organization guidelines, and then LCNECs were separated from atypical carcinoids according to modified criteria using the Ki-67-labeling index and mitotic count. Clinical information and survival data were obtained, and immunohistochemical studies for p53 were conducted. The 5-year survival rates for the 2 typical carcinoids, 7 atypical carcinoids, 7 LCNECs, and 7 small cell carcinomas were 100.0%, 83.3%, 21.4%, and 20.8%, respectively (P=0.032). The LCNEC patients were older (mean age, 61 vs. 41 y; P=0.038), more commonly in advanced stage (stages III and IV 100% vs. 28.6%, P=0.01), with a poorer prognosis (5-year survival 21.4% vs. 83.3%, P=0.03), and more commonly had tumors overexpressing p53 (85.7% vs. 0%, P=0.005) as compared with atypical carcinoid patients. LCNECs should be separated from atypical carcinoids as a new entity of neuroendocrine carcinoma in the head and neck region. The new classification may provide better risk stratification and useful information for proper treatment.
In this paper, we present a copper(I)-catalyzed nitrile-addition/
-arylation ring-closure cascade for the synthesis of 5,11-dihydro-6
-indolo3,2-
quinolin-6-ones from 2-(2-bromophenyl)-
...-(2-cyanophenyl)acetamides. Using CuBr and
-BuONa in dimethylformamide (DMF) as the optimal reaction conditions, the cascade reaction gave the target products, in high yields, with a good substrate scope. Application of the cascade reaction was demonstrated on the concise total syntheses of alkaloid isocryptolepine. Further optimization of the products from the cascade reaction led to 3-chloro-5,12-bis2-(dimethylamino)ethyl-5,12-dihydro-6
-1,3dioxolo4',5':5,6indolo3,2-
quinolin-6-one (
), which exhibited the characteristic DNA topoisomerase-I inhibitory mechanism of action with potent in vitro anticancer activity. Compound
actively inhibited ARC-111- and SN-38-resistant HCT-116 cells and showed in vivo activity in mice bearing human HCT-116 and SJCRH30 xenografts. The interaction of
with the Top-DNA cleavable complex was revealed by docking simulations to guide the future optimization of 5,11-dihydro-6
-indolo3,2-
quinolin-6-ones as topoisomerase-I inhibitors.
A series of pyrrole−indolin-2-ones were synthesized, and their inhibition profile for Aurora kinases was studied. The potent compound 33 with phenylsulfonamido at the C-5 position and a carboxyethyl ...group at the C-3′ position selectively inhibited Aurora A over Aurora B with IC50 values of 12 and 156 nM, respectively. Replacement of the carboxyl group with an amino group led to compound 47, which retained the activity for Aurora B and lost activity for Aurora A (IC50 = 2.19 μM). Computation modeling was used to address the different inhibition profiles of 33 and 47. Compounds 47 and 36 (the ethyl ester analogue of 33) inhibited the proliferation of HCT-116 and HT-29 cells and suppressed levels of the phosphorylated substrates of Aurora A and Aurora B in the Western blots.
Pyrrole–5-(2,6-dichlorobenzyl)sulfonylindolin-2-ones of scaffold 4 with various C-3′ side chains were designed as potent Met kinase inhibitors. Structural optimization led to compounds 10 , 20 , and ...22–24 which demonstrated subnanomolar IC 50 values in the biochemical assay. The potent compound 20 inhibited Met with IC 50 value of 0.37 nM and the proliferation of MKN45 cells with IC 50 of 0.22 μM. It suppressed Met autophosphorylation with the downstream signaling through Gab-1, PLC-γ, FAK, Akt, STAT3, and ERK in cell. Complete inhibition of STAT3 and ERK phosphorylation was observed in MKN45 cells treated with 20 at the concentration of 100 nM. A computation simulation study was performed to reveal the interaction of 20 with Met.
A series of 3-
O-acylated (–)-epigallocatechins were synthesized and their inhibition of steroid 5α-reductase was studied. They were prepared from the reaction of EGCG with
tert-butyldimethylsilyl ...chloride followed by reductive cleavage of the ester bond. The resultant (–)-epigallocatechins penta-
O-
tert-butyldimethylsilyl ether was esterified with different fatty acids then desilylated to provide the corresponding products. The activity of 3-
O-acylated (–)-epigallocatechins increased with the increasing carbon numbers of the fatty acid moiety, reaching maximum for 16 carbon atoms (compound
4h) with an IC
50 of 0.53 μM, which was ∼12-fold more potent than EGCG (IC
50 = 6.29 μM). Introduction of monounsaturated fatty acid provided the most potent compound
6 (IC
50 = 0.48 μM), which showed moderate anti-tumor activity
in vivo.
Introduction of fatty acid to the C3-O position of (–)-epigallocatechin increases the potency for the inhibition of steroid 5α-reductase.
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► Synthesis of 3-
O-acylated (–)-epigallocatechins is accomplished by use of TBMDSCl as the protecting group. ► 3-
O-Acylated (–)-epigallocatechins inhibit 5α-reductase with submicromolar IC
50 values. ► 3-
O-Acylated (–)-epigallocatechin shows moderate anti-tumor activity
in vivo.
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