Design, synthesis, and biological evaluation of indole carboxylic acid esters of podophyllotoxin as antiproliferative agents

Chemistry and Biology of Podophyllotoxins: An Update

“…Later, in order to form the main diastereoisomers 42, compound 41 was followed by a crotonisation with 3,4,5-trimethoxybenzaldehyde. The desilylation of compound 42 was followed by a reductive Heck reaction, which constructed (À )-isopodophyllotoxin (43) with a yield of 64 %. Compound 44 was obtained from 42 by a Heck reaction.…”

“…Compound 130 i exhibited strong antiproliferative activity (IC 50 = 0.227 � 0.011 μM) against drug-resistant cells by induction of cellular autophagy and inhibition of PI3 K/AKT/mTOR, P38 and ERK signaling. [43] As depicted in Scheme 12, Wu et al prepared a series of podophyllotoxin ester derivatives (131 a-131 g) by reaction of PPT with Boc-amino acids. Compound 131 b (sarcosine derivative containing Boc group) induced cancer cell apoptosis and exhibited high anticancer activities, while its toxicity to normal cells was low, showing high selectivity for both.…”

“…The molecular docking studies suggested that compounds 161 c and 161 f may act on microtubule proteins. [62] [57,58] [43] 130 i HeLa HT29 0.070 μM 0.10 μM [50] 139 j MCF-7 0.230 � 0.081 μM [53] 143 b MCF-7 A549 0.130 � 0.087 μM 0.10 � 0.072 μM [53] 143 e HepG2 A549 0.130 � 0.05 μM 0.160 � 0.06 μM [54] Table 1. continued Compound Cancer cell line IC 50 values MCF-7 A549 HeLa HepG2 0.070 � 0.0 μM 0.080 � 0.0 μM 0.080 � 0.0 μM 0.10 � 0.01 μM [55] 147 c MCF-7 HL-7702 A549 HeLa 0.080 � 0.01 μM 0.180 � 0.01 μM 0.140 � 0.03 μM 0.140 � 0.04 μM [56] 148 e HSC-2 SCC-9 A253 0.226 � 0.021 μM 0.231 � 0.05 μM 0.250 � 0.019 μM [57] 151 b HL-60 SMMC-7721 0.130 μM 0.230 μM [58] 152 a HeLa 0.50 � 0.32 μM [59] As illustrated in Scheme 22, compounds 184 a-d were obtained by selective removal of 6,7-methylenedioxy and methylation of compounds 1 and 162 a-c. Then compounds 1, 162 a-c, and 184 a-d reacted with chlorocarbonyl ferrocene/ ferrocenylacetic acid to afford PPT esters containing the ferrocene fragment (185(a-d)-188(a-d)).…”

“…[105] Most of the current structural modifications to PPT were focused on the C ring, and modification of the OH at the C-4 position can lead to anticancer candidates with improved activities. [106] For example, introduction of heterocycles such as 1,3,4-oxadiazole, [41] indole, [43] triazole, [50] aurone, [53] piperazinyl-cinnamic amide, [56] and coumarins [57] to the C-4 position maintained effective anticancer activities. The C-4 position can adapt to diverse structures, and the anticancer activities and the inhibition activity against DNA topoisomerase II were enhanced when the C-4 position had the larger substituents.…”

Research status of indole-modified natural products

“…In addition, compound 41 (resistance factor value: 2.27) also displayed a lower resistance factor in K562/VCR cells, which was comparable to podophyllotoxin (resistance factor value: 2.00) but much lower than VP-16 (resistance factor value: 15.497) and VCR (resistance factor value: 26.612). 75 Derivative 42 (Fig. 5, Table 5, IC 50 : 0.034 μM; the resistance factor values of compound 42, podophyllotoxin, VP-16, and VCR were 2.23, 2.00, 15.49, and 26.61, respectively) showed a lower RSC Medicinal Chemistry Review resistance factor against K562/VCR, and exhibited promising anti-proliferative activity against K562 cancer cells, being more potent than VP-16 (IC 50 : 0.764 μM) and VCR (IC 50 : 0.178 μM), and comparable to podophyllotoxin (IC 50 : 0.025 μM).…”