title: Comparison of the crystal structures of the potent anticancer and anti-angiogenic agent regorafenib and its monohydrate.
abstract: Regorafenib {systematic name: 4-[4-({[4-chloro-3-(trifluoromethy)phenyl]carbamoyl}amino)-3-fluorophenoxy]-1-methylpyridine-2-carboxamide}, C21H15ClF4N4O3, is a potent anticancer and anti-angiogenic agent that possesses various activities on the VEGFR, PDGFR, raf and/or flt-3 kinase signaling molecules. The compound has been crystallized as polymorphic form I and as the monohydrate, C21H15ClF4N4O3·H2O. The regorafenib molecule consists of biarylurea and pyridine-2-carboxamide units linked by an ether group. A comparison of both forms shows that they differ in the relative orientation of the biarylurea and pyridine-2-carboxamide units, due to different rotations around the ether group, as measured by the C-O-C bond angles [119.5 (3)° in regorafenib and 116.10 (15)° in the monohydrate]. Meanwhile, the conformational differences are reflected in different hydrogen-bond networks. Polymorphic form I contains two intermolecular N-H...O hydrogen bonds, which link the regorafenib molecules into an infinite molecular chain along the b axis. In the monohydrate, the presence of the solvent water molecule results in more abundant hydrogen bonds. The water molecules act as donors and acceptors, forming N-H...O and O-H...O hydrogen-bond interactions. Thus, R4(2)(28) ring motifs are formed, which are fused to form continuous spiral ring motifs along the a axis. The (trifluoromethyl)phenyl rings protrude on the outside of these motifs and interdigitate with those of adjacent ring motifs, thereby forming columns populated by halogen atoms.
authors.affiliation: College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, People's Republic of China.
authors.forename: Meng Ying
authors.initials: MY
authors.lastname: Sun
authors.affiliation: College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, People's Republic of China.
authors.forename: Su Xiang
authors.initials: SX
authors.lastname: Wu
authors.affiliation: College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, People's Republic of China.
authors.forename: Xin Bo
authors.initials: XB
authors.lastname: Zhou
authors.affiliation: Chemistry Department, Zhejiang University, Hangzhou, Zhejiang 310028, People's Republic of China.
authors.forename: Jian Ming
authors.initials: JM
authors.lastname: Gu
authors.affiliation: Chemistry Department, Zhejiang University, Hangzhou, Zhejiang 310028, People's Republic of China.
authors.forename: Xiu Rong
authors.initials: XR
authors.lastname: Hu
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D006860:Hydrogen Bonding; D015394:Molecular Structure; D010671:Phenylurea Compounds / Q000737:chemistry* / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology; D012997:Solvents / Q000737:chemistry
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D011725:Pyridines; D012997:Solvents; C559147:regorafenib
keywords: anti-angiogenic agent; anticancer agent; crystal structure; hydrogen bonding; pharmaceutical compounds; polymorph; regorafenib