GHK (Gly‐His‐Lys), a natural peptide found in human skin and plasma, has been widely used in the cosmeceutical and pharmaceutical fields. The hydrophilic GHK and GHK‐Cu are limited in their abilities to penetrate deeply into skin; because of this, various strategies for their skin delivery have been developed. In this investigation, Arg4 was conjugated with GHK to get heptapeptide, GHK‐R4, and then in vitro antiwrinkle activity and transdermal delivery were compared between GHK and GHK‐R4. Notably, Arg4 conjugation accelerated the cellular penetration of GHK both in vitro and in vivo. Furthermore, higher in vitro antiwrinkle activity and collagen biosynthesis was obtained with GHK‐R4 at much lower doses than with control R4‐free GHK. The enhanced activity and delivery of GHK‐R4 might be due to the cell penetrating ability and matrix metalloproteinase (MMP) inhibitory activity of R4 itself.

03 Aug 2018·The Journal of Organic ChemistryQ2 · CHEMISTRY

Total Synthesis of γ-Alkylidenebutenolides, Potent Melanogenesis Inhibitors from Thai Medicinal Plant Melodorum fruticosum

Q2 · CHEMISTRY

Article

Author: Ishikawa, Fumihiro ; Ogawa, Teppei ; Ninomiya, Kiyofumi ; Manse, Yoshiaki ; Chaipech, Saowanee ; Pongpiriyadacha, Yutana ; Marumoto, Shinsuke ; Tanabe, Genzoh ; Muraoka, Osamu ; Morikawa, Toshio ; Sonoda, Naoki

A hitherto unreported member of γ-alkylidenebutenolides in Melodorum fruticosum (Annonaceae), (4 E)-6-benzoyloxy-7-hydroxy-2,4-heptadiene-4-olide, named as isofruticosinol (4) was isolated from the methanol extract of flowers, along with the known related butenolides, namely, the (4 Z)-isomer (3) of 4, melodrinol (1), and its (4 E)-isomer (2). To unambiguously determine the absolute configuration at the C-6 position in these butenolides, the first total syntheses of both enantiomers of 2-4 were achieved over 6-7 steps from commercially available D- or L-ribose (D- and L-5). Using the same protocol, both enantiomers of 1 were also synthesized. Based on chiral HPLC analysis of all synthetic compounds ( S- and R-1-4), all naturally occurring butenolides were assigned as partial racemic mixtures with respect to the chiral center at C-6 (enantiomeric ratio, 6 S/6 R = ∼83/17). Furthermore, the melanogenesis inhibitory activities of S- and R-1-4 were evaluated, with all shown to be potent inhibitors with IC₅₀ values in the range 0.29-2.9 μM, regardless of differences in the stereochemistry at C-6. In particular, S-4 (IC₅₀ = 0.29 μM) and R-4 (0.39 μM) showed potent inhibitory activities compared with that of reference standard arbutin (174 μM).

04 May 2018·Expert Opinion on Drug DeliveryQ2 · MEDICINE

Low density, good flowability cyclodextrin-raffinose binary carrier for dry powder inhaler: anti-hygroscopicity and aerosolization performance enhancement

Q2 · MEDICINE

Article

Author: Wang, Guanlin ; Freeman, Tim ; Huang, Zhengwei ; Huang, Ying ; Cui, Yingtong ; Wu, Chuanbin ; Pan, Xin ; Zhao, Ziyu ; Lu, Xiang-yun ; Ma, Cheng ; Zhang, Xuejuan

BACKGROUNDThe hygroscopicity of raffinose carrier for dry powder inhaler (DPI) was the main obstacle for its further application. Hygroscopicity-induced agglomeration would cause deterioration of aerosolization performance of raffinose, undermining the delivery efficiency.METHODSCyclodextrin-raffinose binary carriers (CRBCs) were produced by spray-drying so as to surmount the above issue. Physicochemical attributes and formation mechanism of CRBCs were explored in detail. The flow property of CRBCs was examined by FT4 Powder Rheometer. Hygroscopicity of CRBCs was elucidated by dynamic vapor sorption study. Aerosolization performance was evaluated by in vitro deposition profile and in vivo pharmacokinetic profile of CRBC based DPI formulations.RESULTSThe optimal formulation of CRBC (R₄) was proven to possess anti-hygroscopicity and aerosolization performance enhancement properties. Concisely, the moisture uptake of R₄ was c.a. 5% which was far lower than spray-dried raffinose (R₀, c.a. 65%). R₄ exhibited a high fine particle fraction value of 70.56 ± 0.61% and it was 3.75-fold against R₀. The pulmonary and plasmatic bioavailability of R₄ were significantly higher than R₀ (p < 0.05).CONCLUSIONCRBC with anti-hygroscopicity and aerosolization performance enhancement properties was a promising approach for pulmonary drug delivery, which could provide new possibilities to the application of hygroscopic carriers for DPI.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	CN	Shanghai Yunying Medical Technology Co., Ltd.Startup	30 Nov 2023

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