# Diparlureas as Antitumor Agents
## 3 Other Diparlures  
In this paragraph several studies on other diparlures are described (Table 1). [PERSON] et al. synthesized several diparlurea derivatives in order to study their cytostatic activity [95]. The compounds were tested on tumor cell lines: HCT 116 (colon carcinoma), SW 620 (colon carcinoma), MCF-7 (breast carcinoma), H460 (lung carcinoma), L1210 (murine leukemia), CEM (human lymphoma), and HeLa (cervix carcinoma). Compounds **1a-e** exerted the highest effect (IC\({}_{50}\) from 1 to 4.3 uM, with an average of 2.6 \(\pm\) 1.6 uM) even though with low selectivity for the different tumor cell lines. The compounds were also cytostatic against primary human embryonic lung (HEL) fibroblast cells. [PERSON] et al. [11] studied a series of water-soluble \(N\)-mustard-benzene conjugates containing a urea linker. The urea linker was introduced in order to overcome the low solubility of compounds previously studied. The authors studied a series of water-soluble \(N\)-mustards, in which the phenyl \(N\)-mustard is linked to a benzene ring through a urea linker. In particular, the diarylurea **2** (BO-1055), as the hydrochloride salt, exhibited high in vitro cytotoxicity and therapeutic efficacy against various human tumor cell lines. It was demonstrated to possess potent therapeutic effect against several human solid tumor cell lines, including human breast cancer (MX-1), colon cancer (HCT-116), and prostate cancer (PC3), in xenograft model. The DNA repair capacity of compound BO-1055, named ureidomustin, was then studied. It was proposed for the treatment of tumors with deficient nucleotide excision repair (NER), homologous recombination (HR), and O\({}^{6}\)-methylguanine-DNA methyltransferase (MGMT) DNA repair genes, or in synergy with other drugs in tumors in which DNA damage response has been repressed [96].BO-1055 was also proposed as a therapeutic agent for Ewing sarcoma and rhabdomyosarcoma given its potency and relative lack of toxicity against normal tissue [97]. It also showed a potent activity against B-cell lymphomas, as mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL) [98]. In a following paper, the same research group indicated that compound **2** has a quite narrow therapeutic window; thus, following a biososteric approach, an inversion of the carboxamide functionality was addressed. Compound **3** was superior to compound **2** against colon cancer (HCT-116) and lung cancer (H460) cell lines, and displayed minor toxicity. Cotreatment of compound **3** and 5-fluorouracilcell suppressed the growth of HCT-116 xenografts. Moreover, compound **3** could induce DNA cross-linking and cell-cycle arrest at the G2/M phase. This compound was selected for early preclinical studies [99]. A series of diarylureas was studied for in vitro antiproliferative activities against HepG2, MGC-803, and A549 cancer cell lines [100]. Compound **4** displayed optimal antiproliferative activity against the three cell lines in comparison with sorafenibb and gefitinib. Indeed, it induced A549 cells apoptosis through the cell cycle block at the G0/G1 phase, the increase of intracellular reactive oxygen species, and the reduction of mitochondrial membrane potential. This compound also influenced the Raf/MEK/ERK pathway. A series of diarylureas derivatives was studied for its cytotoxicity in vitro against H-460, HT-29, A549, and MDA-MB-231 cancer cell lines [101]. Some of them showed higher activity than sorafenibb (IC\({}_{50}\) between 0.089 and 5.46 \(\upmu\)M). In particular, compound **5** was the most potent both in cellular (IC\({}_{50}\) = 0.15, 0.089, 0.36, and 0.75 \(\upmu\)M, respectively) and enzymatic assay (IC\({}_{50}\) = 56 nM against EGFR). The antiproliferative activity of diarylureas bearing a 4-anilinoquinazoline group was evaluated via MTT assay against A431 and A549 cells [102]. Three compounds showed high antiproliferative activities and their inhibitory activity against EGFR-TK was evaluated. Compound **6** was a potent EGFR-TK inhibitor.