# Diparlureas as Antitumor Agents
## 3 Other Diparlures
This completely inhibited cancer growth in established nude mouse A549 xenograft model in vivo, at 50 mg/kg. Daryllureas were studied as LIM-kinase (Limk) inhibitors for their therapeutic potential against prostate cancers [103]. Limk is a serine-threonine protein kinase existing in two isoforms, LIM kinase 1 (Limk1) and LIM kinase 2 (Limk2). The inhibition of Limk1 activity in cancer prostate cells and tissues determines reduction of phosphorylated cofilin and cancer cells motility, thus reducing invasiveness of the tumor and evolution to metastasis. The substituted diarylureas **7**, at 1 \(\upmu\)M, inhibited only Limk1 and STK16 with \(\geq\)80% inhibition. The use of Limk inhibitors has been also suggested to target the invasive machinery in GBM [104]. Recently, a diarylurea, N69B, was evaluated for its anticancer activity and its molecular mechanism was investigated [105]. The compound was shown to inhibit proliferation of murine and human cancer cells in vitro, and reduce tumor growth in mouse 4T1 breast tumor model in vivo. Compound N69B significantly increased protein levels of cathepsin, in particular cathepsin D, a lysosomal aspartyl protease with various biological functions. Several diarylureas bearing a coumarine moiety [106; 107] have been recently tested for their in vitro antiproliferative activities against the H4 IIE and HepG2 cancer cell lines, and has been proposed as a promising lead for further optimization [108]. Compound **8b** exhibited a higher inhibition of H4 IIE cells compared to sorafenibb. **8a** also showed a better inhibition against HepG2 cells than sorafenibb. In particular, **8b** arrested cell cycle at the S phase and induced H4 IIE cells apoptosis. A library of diarylureas has been designed and the in vitro antiproliferative activities was studied against HT-29 and A549 cancer cell lines. Compound **9** was the most active against HT-29 cells showing an IC\({}_{50}\) value of 3.38 uM, compared to that of sorafenib (IC\({}_{50}\) = 17.28 uM). It induced cell cycle arrest at G\({}_{0}\)/G\({}_{1}\) phase, interfered with Raf/MEK/ERK signaling pathway, increased intracellular reactive oxygen species level, and led to HT-29 cells apoptosis [109]. The same research group studied a series of benzo[\(b\)]thiophene-diarylureas with potential anticancer effects, too. Compound **10** was the most active (IC\({}_{50}\) = 5.91 and 14.64 uM on HT-29 and A549 cells, respectively). It induced apoptosis and cell cycle arrest at the G0/G1 phase on HT-29 cells, too [110]. Several diphenyllazoles, containing diarylurea moieties, in the low micromolar range, inhibited cell viability of various cancer cell lines including murine metastatic breast cancer 4T1, murine glioma GL261-luc2, human triple negative breast cancer MDA-MB-231, human pancreatic cancer MIAPCa-2, and human colorectal adenocarcinoma WiDr. The lead candidate **11** significantly reduced the tumor growth in aggressive stage IV breast cancer 4T1 syngraft model in vivo [111]. A series of diarylureas bearing a substituted thiadiazole as one of the two aryl moieties was studied against human chronic myeloid leukemia (CML) cell line K562. The diarylurea **12** exhibited the least cytotoxicity and higher biological activity (IC\({}_{50}\) = 0.038 uM). It also displayed good induced-apoptosis effect for human CML cell line K562; its effect seems to happen via a significant reduction of protein phosphorylation of PI3K/AKT signal pathway by human phospho-kinase array analysis [112]. Forchlorforneuron (FCF; N-(2-Chloro-4-pyridyl)-N'-phenylurea) is a small synthetic diarylurea currently used in agriculture as a plant fertilizer that increases fruit size because of its potent cytokin activity. FCF inhibits proliferation, anchorage-independent growth, migration, and invasion of cancer cell lines in various cancer types, such as prostate, mesothelioma, lung, colon, breast, ovary, and cervix [113]. FCF was also found to be effective in a mouse model, in which tumor growth was inhibited.