1,4-Naphthoquinones as inhibitors of Itch, a HECT domain-E3 ligase, and tumor growth suppressors in multiple myeloma.

A series of 1,4-naphthoquinones (10a-10q) were synthesized and evaluated for anticancer activity. Compound 10e was identified as an inhibitor of Itch, a HECT domain-E3 ligase. In an evaluation of in vivo efficacy, 10e exhibited remarkable anticancer activity with TGI values of 98.3% and 100% at 25 mg/kg and 50 mg/kg orally daily, respectively, against human RPMI-8226 multiple myeloma xenograft. Treatment with 10e also showed a decrease of Itch level in human RPMI-8226 multiple myeloma cells. Thus 10e is a lead compound for further development of inhibitors targeting E3 ligase for treatment of multiple myeloma.

Synthesis and protective effects of bis{4-[N,N-di-(carboxymethyl)amino]phenoxy}alkane derivatives on UVA-induced production of MMP-1 in human skin fibroblasts.

UV-induced matrix metalloproteinase (MMP) production is considered a cause of skin aging. In this study, a number of novel bis{4-[N,N-di-(carboxymethyl)amino]phenoxy}alkane derivatives were synthesized and evaluated as UVA-protective agents. These compounds significantly protected human dermal fibroblast (HDF) cells from UVA-induced cytotoxicity and inhibited MMP-1 activation and expression with potency comparable to desferoxamine (DFO). Promoter activity assay indicated that they inhibited MMP-1 expression at the transcriptional level. Further studies revealed that the mechanism of these compounds may include blockage of the UVA-induced activation of the p38/mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) pathways. Together, these results suggest that further development of these compounds may be of interest.

Furanylazaindoles: potent anticancer agents in vitro and in vivo.

Preliminary biological data on 7-anilino-6-azaindoles (8-11) suggested that hydrophobic substituents at C7 contribute to enhancement of antiproliferative activity. A novel series of 7-aryl-6-azaindole-1-benzenesulfonamides (12-22) were developed and showed improved cytotoxicity compared to ABT751 (5). The conversion of C7 phenyl rings into C7 heterocycles led to a remarkable improvement of antiproliferative activity. Among all the synthetic products, 7-(2-furanyl)-1-(4-methoxybenzenesulfonyl)-6-azaindole (21) exhibited the most potent anticancer activity against KB, HT29, MKN45, and H460 cancer cell lines with IC50 values of 21.1, 32.0, 27.5, and 40.0 nM, respectively. Bioassays indicated that 21 not only inhibits tubulin polymerization by binding to tubulin at the colchicine binding site but also arrests the cell cycle at the G2/M phase with slight arrest at the sub-G1 phase. Compound 21 also functions as a vascular disrupting agent and dose-dependently inhibits tumor growth without significant change of body weight in an HT29 xenograft mouse model. Taken together, compound 21 has potential for further development as a novel class of anticancer agents.

Application of Suzuki arylation, Sonogashira ethynylation and Rosenmund-von Braun cyanation in the exploration of substitution effects on the anticancer activity of 2-aroylquinolines.

A variety of functionalities were introduced at 2-aroylquinoline's C5 position, which is considered equivalent to C-3' of the B-ring of CA4, via Suzuki arylation, Sonogashira ethynylation, and Rosenmund-von Braun cyanation. These substitutions are rarely utilized in the modification of 3'-OH of CA4. The resulting products 6 and 7 having cyano and ethynyl groups exhibited comparable antiproliferative and tubulin inhibitory activities to colchicine.

5-Amino-2-aroylquinolines as highly potent tubulin polymerization inhibitors. Part 2. The impact of bridging groups at position C-2.

A variety of studies on the modification of combretastatin A-4 triggered our interest in the impact of the linkers between the 3,4,5-trimethoxyphenyl ring and 5-amino-6-methoxyquinoline on biological activity. The replacement of the carbonyl group with bond, amine, ether, sulfide, and sulfone groups was evaluated in this study. The results showed that compounds 14 and 15 containing sulfide and sulfone groups between the 3,4,5-trimethoxyphenyl ring (A-ring) and 5-amino-6-methoxyquinoline exhibited substantial antiproliferative activity against KB, HT29, and MKN45 cells with mean IC50 values of 42 and 12 nM, respectively. 15 inhibited the tubulin polymerization with an IC50 value of 2.0 µM, similar to that with CA4. The continued work on the C-5 substituents of 3',4',5'-trimethoxybenzoyl-6-methoxyquinoline derivatives demonstrated that compound 7 possessing OH at C-5 exhibited excellent antiproliferative activity with mean IC50 values of 3.4 nM and microtubule destabilizing potency with an IC50 of 1.5 µM, comparable to that of CA4 (IC50=1.9 µM). It also exhibited substantial vascular disrupting effects. Compounds 7 and 15 exhibited significant efficacy against MDR/MRP-related drug-resistant cell lines (KB-vin10, KB-S15, and KB-7D) with mean IC50 values of 6.7 and 2.6 nM, respectively.

Synthesis and biological evaluation of 4-aroyl-6,7,8-trimethoxyquinolines as a novel class of anticancer agents.

A series of 2-aroyl and 2-aryl-5,6,7-trimethoxyquinoline and 4-aroyl-6,7,8-trimethoxyquinoline combretastatin analogs were synthesized and evaluated for their potential anticancer activity. The 4-aroylquinoline 11 inhibited the growth of the human cancer cells lines KB, HT-29, and MKN45, as well as the three human resistant cancer cell lines KB-vin10, KB-S15, and KB-7D, with IC50 values of 217, 327, 239, 246, 213, and 252 nM, respectively.

5-Amino-2-aroylquinolines as highly potent tubulin polymerization inhibitors.

A series of aroylquinoline derivatives were synthesized and evaluated for anticancer activity. 5-Amino-6-methoxy-2-aroylquinoline 15 showed more potent antiproliferative activity (IC(50) values ranging from 0.2 to 0.4 nM) as compared to 1a (combretastatin A-4) (IC(50) = 1.9-835 nM) against various human cancer cell lines and a MDR-resistant cancer cell line. Compound 15 (IC(50) = 1.6 microM) exhibited more potent inhibition of tubulin polymerization than 1a (IC(50) = 2.1 microM) and showed strong binding property to the colchicine binding site of microtubules.