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Natural products originating from plants have various beneficial pharmacological effects, such as anticancer, antimicrobial, and anti-inflammatory activities, while being nontoxic. Therefore, tremendous efforts have been invested in understanding their bioactivities in the body to facilitate therapeutic target validation. However, such research is still challenging for certain natural products, such as flavonoids, which are rapidly metabolized in and eliminated from the human body. To investigate the bioactivities of such products, particularly in certain tissues, it is necessary to understand their biodistribution in vivo. In this respect, reliable analytical methods with simple and efficient procedures for the in vivo evaluation of natural small molecules are urgently required. In particular, mass spectrometry (MS) can be effectively used to analyze small molecules after tissue extraction, as MS has various advantages including accuracy, simplicity, and high sensitivity. Herein, we report the biodistribution of a natural small molecule by using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). After intravenously injecting gomisin H into a mouse as a model natural product, it was extracted from each organ and then analyzed by MALDI-TOF MS. The analysis showed that gomisin H accumulated mainly in the liver and relatively large amounts of the product existed in the kidney and brain compared to those in other tissues.

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-5-mercapto-3H-1,3,4-thiadiazoline † This paper is dedicated to the memory of Prof. Chi-Sun Hahn.The design and synthesis of new class of macrocycles with novel shapes and heterocyclic moiety continue to be the topics of current interest, 1 because they can act as a ligand in asymmetric catalysis 2 and as a host molecule for the incorporation of guest molecule or ions.3 While 1,3,4-thiadizoles have received attention as a sulfur donor subunit, 4 very little is known about the corporation of heterocylic compounds into macrocyclic compounds.1a,5 As part of our systematic efforts1 6 aimed at the synthesis of new macrocyclic ligands fused with 1,3,4-thiadiazoles, we reported 6e our attempt to synthesize novel macrocycles that incorporate 2-imino-5-mercapto-3H-1,3,4-thiadiazolines. Imino group and mercapto group of 2-imino-5-mercapto-3H-1,3,4-thiadiazoline might show novel role when the molecule works as a host for the corporation of a guest molecule.As part of the ongoing study of heterocycles containing 2-imino-5-mercapto-3H-1,3,4-thiadiazolines, we report here the synthesis of macrocycles (4a, 4b, 4c, 4d, 4e, and 4f) containing two 2-imino-5-mercapto-3H-1,3,4-thiadizoline subunits linked at the 3-and 5-positions of the heterocyclic unit. The macrocycles were prepared from 1, as shown in Scheme 1. The spacers between 5 and 5' are CH2CH2, (CH2CH2)2O, and m-xylene, respectively, and the 3-3' spacer is (CH 2 CH 2 ) 2 Compound (1) was regiospecifically S-alkylated under basic conditions, to give 5-amino-2-alkylthio-1,3,4-thiadiazole (2). 6e,7 In addition, 5-substituted 2-acylamino-1,3,4-thiadiazoles (3) were also regiospecifically alkylated at the N(3) position under basic conditions to yield a single 3-alkylated endo-product. 6e,8 These reactions were used for macrocycle ring formation.Compound 2 was synthesized from 1 according the above procedure with an appropriate α,ω-dibromoalkane in the presence of KOH in ethanol to yield the S-alkylated dimer (2). Benzolylation of the amino group of 2 (7.2 -7.3 ppm) was performed to create 3. As evidenced by spectroscopic data, this reaction regiospecifically alkyalted the N(3) position of 3 at the NH 2 (endo-product), as has been observed in the benzoylation of 2-amino-5-alkylthio-1,3,4-thiadiazoles. 6e,8 In 3b, the NH2 signals characteristic of compound 2b were replaced by typical NHCOPh signals appearing at 13.12 and at 8. 12-7.54, 165.2, 133.0, 131.2, 128.6, and at 128.3 ppm in the 1 H and 13 C NMR spectra, respectively. In the 13 C NMR spectrum, the chemical shifts of C(2) and C(5) in the 1,3,4-thiadiazole of 2b (150.0 and 169.5 ppm) changed to those of 3b (159.5 and 159.0 ppm), as observed for 2-amino-5-alkylthio-1,3,4-thiadizole and 2-benzoylamino-5-alkylthio-1,3,4-thiadiazole. Furthermore, a characteristic carbonyl band was observed in the IR spectrum at 1661 cm -1 and in the 13 C NMR spectrum at 165.2 ppm. As expected, the cyclization reaction, which was facilitated by N,Nbisalkylation between the benzolylated compound (3) and the appropriate α,ω-dibromoalkan...