Improving the Membrane Permeability of 5-Fluorouracil via Cocrystallization

Dai, Xiaoling; Li, Song; Chen, Jiamei; Lu, Tong‐Bu

doi:10.1021/acs.cgd.6b00552

Cited by 91 publications

(80 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One hydrogen of the guest ammonium ion is too far away to form a strong hydrogen bond to the nearest host amine nitrogen, and therefore makes a closer contact to a fluorine atom. In the cocrystal structure IQILAX (Dai et al, 2016), an N-HÁ Á ÁF-C interaction is a small compromise in an otherwise almost perfect and rather beautiful hydrogen-bonding network (Fig. 13).…”

Section: Short X-há á áF-c Hydrogen Bondsmentioning

confidence: 99%

The hydrogen bond between N—H or O—H and organic fluorine: favourable yes, competitive no

Taylor

2017

Acta Crystallogr B Struct Sci Cryst Eng Mater

View full text Add to dashboard Cite

A study was made of X-H...F-C interactions (X = N or O) in small-molecule crystal structures. It was primarily based on 6728 structures containing X-H and C-F and no atom heavier than chlorine. Of the 28 451 C-F moieties in these structures, 1051 interact with X-H groups. However, over three-quarters of these interactions are either the weaker components of bifurcated hydrogen bonds (so likely to be incidental contacts) or occur in structures where there is a clear insufficiency of good hydrogen-bond acceptors such as oxygen, nitrogen or halide. In structures where good acceptors are entirely absent, there is about a 2 in 3 chance that a given X-H group will donate to fluorine. Viable alternatives are X-H...π hydrogen bonds (especially to electron-rich aromatics) and dihydrogen bonds. The average H...F distances of X-H...F-C interactions are significantly shorter for CRF (R = C or H) and Csp-F acceptors than for CRF. The X-H...F angle distribution is consistent with a weak energetic preference for linearity, but that of H...F-C suggests a flat energy profile in the range 100-180°. X-H...F-C interactions are more likely when the acceptor is Csp-F or CRF, and when the donor is C-NH. They also occur significantly more often in structures containing tertiary alcohols or solvent molecules, or with Z' > 1, i.e. when there may be unusual packing problems. It is extremely rare to find X-H...F-C interactions in structures where there are several unused good acceptors. When it does happen, there is often a clear reason, e.g. awkwardly shaped molecules whose packing isolates a donor group from the good acceptors.

show abstract

Section: Short X-há á áF-c Hydrogen Bondsmentioning

confidence: 99%

The hydrogen bond between N—H or O—H and organic fluorine: favourable yes, competitive no

Taylor

2017

Acta Crystallogr B Struct Sci Cryst Eng Mater

View full text Add to dashboard Cite

show abstract

“…The MBA molecules form a hydrogenbonded dimer typical of benzoic acids through the carboxylic acid groups. The 5FU molecules are further connected by MBA dimers via a weak C9-H9Á Á ÁF5 iv (Dai et al, 2016) hydrogen bond to generate a supramolecular ribbon ( Fig. 2 and Table 2).…”

Section: Resultsmentioning

confidence: 99%

“…5FU acts against cancer by inhibiting thymidylate synthase, which in turn stops the production of the thymine required by the cancerous cell for the production of DNA. Various crystal structures of cocrystals and complexes of 5FU have been reported in the literature (Fallon, 1973;Hulme & Tocher, 2004;Hulme & Tocher, 2005a,b;Barnett et al, 2006;Portalone & Colapietro, 2007;Delori et al, 2013;Li et al., 2014;Dai et al, 2016). Pyrimidine derivatives are biologically important compounds.…”

Section: Introductionmentioning

confidence: 99%

Supramolecular hydrogen-bonding patterns in 1:1 cocrystals of 5-fluorouracil with 4-methylbenzoic acid and 3-nitrobenzoic acid

Mohana

Muthiah

McMillen

2017

Acta Crystallogr C Struct Chem

View full text Add to dashboard Cite

The design of a pharmaceutical cocrystal is based on the identification of specific hydrogen-bond donor and acceptor groups in active pharmaceutical ingredients (APIs) in order to choose a `complementary interacting' molecule that can act as an efficient coformer. 5-Fluorouracil (5FU) is a pyrimidine derivative with two N-H donors and C=O acceptors and shows a diversity of hydrogen-bonding motifs. Two 1:1 cocrystals of 5-fluorouracil (5FU), namely 5-fluorouracil-4-methylbenzoic acid (5FU-MBA), CHFNO·CHO, (I), and 5-fluorouracil-3-nitrobenzoic acid (5FU-NBA), CHFNO·CHNO, (II), have been prepared and characterized by single-crystal X-ray diffraction. In (I), the MBA molecules form carboxylic acid dimers [R(8) homosynthon]. Similarly, the 5FU molecules form two types of base pair via a pair of N-H...O hydrogen bonds [R(8) homosynthon]. In (II), 5FU interacts with the carboxylic acid group of NBA via N-H...O and O-H...O hydrogen bonds, generating an R(8) ring motif (heterosynthon). Furthermore, the 5FU molecules form base pairs [R(8) homosynthon] via N-H...O hydrogen bonds. Both of the crystal structures are stabilized by C-H...F interactions.

show abstract

“…Permeability of drugs mainly depends upon the n-octanol/water partition coefficient by using log P and (C log P) for unchanged form of drug [28] . Permeability of a BCS class-III drug, 5-fluorouracil, was enhanced by cocrystallization with different coformers such as 3-hyroxybenzoic acid, 4-aminobenzoic acid and cinnamic acid [57] . Permeability study of hydrochlorothiazide and cocrystals with different coformers was studied by using Franz diffusion cells.…”

Section: Permeabilitymentioning

confidence: 99%