A series of novel podophyllotoxin derivatives were designed using association strategy and synthesized by coupling either podophyllotoxin (1) or 4b b-amino podophyllotoxin (3) with substituted indol-3-yl-glyoxyl chlorides. Their structures were identified using spectroscopic techniques. These novel derivatives have been evaluated for cytotoxicity in vitro against four human cancer cell lines with comparison to the parent compounds 1, 3 and indibulin (2). Some of the compounds (7a, 7c) showed comparable cytotoxicity to that of podophyllotoxin.Key words podophyllotoxin; indibulin; cytotoxicity; multidrug resistance Chem. Pharm. Bull. 56(6) 831-834 (2008) © 2008 Pharmaceutical Society of Japan * To whom correspondence should be addressed. e-mail: mscheng@syphu.edu.cn Fig. 1 We report herein the synthesis and cytotoxicity of a series of 4a-O-and 4b-N-indol-3-yl-glyoxyl-substituted derivatives of podophyllotoxin. The biological activity of these derivatives was evaluated by in vitro cytotoxicity study.Chemistry The novel podophyllotoxin derivatives 7a-j were prepared according to the general synthetic approach as depicted in Chart 2. The N-substituted indoles 5a-c were readily synthesized by the reaction of indole 4 with an aralkyl chloride in the presence of NaH. Treatment of substituted indoles 5 with oxalyl chloride in diethyl ether gave substituted indol-3-yl-glyoxyl chlorides 6 with a 70-95% yield. Subsequently, 6 was coupled with podophyllotoxin or 4b-amino podophyllotoxin in the presence of triethylamine and 4-(N,N-dimethylamino)-pyridine (DMAP) to generate the products listed in Table 1. As illustrated in Chart 2, 4b-amino podophyllotoxin was prepared from podophyllotoxin according to known procedures. 5,13) Acylation of podophyllotoxin retained the a-configuration of its C-4 carbon atom, which could be deduced from the 1 H-NMR spectral data of 7a-c. In their 1 H-NMR spectra, the J value (8.3 Hz) of the hydrogen atom (d 6.05 or 6.06 ppm) at the C-4 position of 7a-c demonstrates their 4a-configuration. The structures of the resulting compounds were identified by 1 H-NMR and mass spectroscopy. Results and DiscussionThe biological activity of this series of podophyllotoxin derivatives was evaluated by an in vitro cytotoxicity test, which was carried out with a panel of four human cancer cell lines including HeLa (cervix), SKOV3 (ovary), K562 (leukemia) and K562ADR (adriamycin resistant leukemia), using podophyllotoxin (1), indibulin (2), 4b-aminopodophyllotoxin (3) and adriamycin as reference compounds. The screening procedure was based on the standard MTT or SRB method. The IC 50 and GI 50 values are shown in Table 2.As can be seen from the results, most of the derivatives presented substantial in vitro cytotoxic activity, even against the adriamycin resistant leukemia cell line (K562ADR). The potency of some of the compounds (7b, 7c, 7f, 7i, 7j) against K562ADR (the resistant multiple was 31.19) was comparable to those against the common K562 cell line. However, two derivatives (7g, 7h) were unable to inh...

Bedaquiline (BDQ) is a novel and highly potent last‐line antituberculosis drug that was approved by the US FDA in 2013. Owing to its stereo‐structural complexity, chemical synthesis and compound optimization are rather difficult and expensive. This study describes the structural simplification of bedaquiline while preserving antitubercular activity. The compound's structure was split into fragments and reassembled in various combinations while replacing the two chiral carbon atoms with an achiral linkage instead. Four series of analogues were designed; these candidates retained their potent antitubercular activity at sub‐microgram per mL concentrations against both sensitive and multidrug‐resistant (MDR) Mycobacterium tuberculosis strains. Six out of the top nine MIC‐ranked candidates were found to inhibit mycobacterial ATP synthesis activity with IC50 values between 20 and 40 μm, one had IC50>66 μm, and two showed no inhibition, despite their antitubercular activity. These results provide a basis for the development of chemically less complex, lower‐cost bedaquiline derivatives and describe the identification of two derivatives with antitubercular activity against non‐ATP synthase related targets.

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Aus Siphonaria zelandica und aus S. atra werden zwei neue SpiroketaIe, Siphonarin A (Ia) und Siphonarin B (Ib), isoliert.

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