Oxygen heterocyclic ring is one of the most common heterocyclic rings in drugs and natural products. By the end of 2017, 311 drug molecules had at least one oxygen heterocyclic ring approved by FDA in the USA, the most common of which were pyran ring, a furan ring, macrolide, morpholine, and dioxane. The 311 drug molecules contained a total of 389 oxygen heterocyclic rings ranging from three-membered to seven-membered. We mainly introduce the drugs containing three-membered ring and four-membered ring, including their mechanism of action, indication, state, and structure.
- According to the ring size statistics, five and six-membered rings account for 46% and 38% respectively, three-, seven- and four-membered rings account for 3%, 2% and 1% respectively.
- According to the statistics of aromaticity, non-aromatic rings account for most of them (89%), and 95% of aromatic rings are five-membered rings.
- According to the number of rings, 71% of the drug molecules contain one oxygen heterocyclic ring, 13% and 6% of the drug molecules contain two and three oxygen heterocyclic rings respectively, and 3% of the drug molecules contain more than eight oxygen heterocyclic rings.
- According to the atomic composition of the ring, 64% of the heterocyclic oxygen consists of multiple carbon atoms and one oxygen atom, and 26% of the heterocyclic oxygen contains simultaneously nitrogen, sulfur, boron, and even metal atoms.
- According to chiral statistics, most of the oxygen heterocyclic rings (75%) are chiral.
Drugs containing ethylene oxide (ternary ring)
Currently, 13 drugs with ethylene oxide structure have been approved by FDA. Among them, eplerenone, trilostane, and picrotoxin contain trisubstituted redox ethane. The disubstituted ethylene oxide can be further divided into three categories: 1-, 1-disubstituted (Carfilzomib and troleandomycin), 1-, 2- trans-disubstituted (natamycin and mupirocin) and 1-, 2-cis-disubstituted (scopolamine, methyl scopolamine, tiotropium, cerulenin, and fosfomycin). Most of these drugs are derived from natural products, in which Troleandomycin, natamycin, mupirocin, scopolamine, and picrotoxin are natural products, while eplerenone, trilostane, tiotropium, and methyl scopolamine are natural derivatives.
Four-membered oxygen heterocyclic drugs
Oxygen heterocyclobutane has high polarity and is a good hydrogen bond acceptor, which contributes to the metabolic and chemical stability of its host molecules. In recent years, oxacyclo butane has been proved to be a dimethyl and carbonyl bioelectronic isosteric species. Four drugs approved by the FDA in the United States contain oxirane, orlistat, paclitaxel and two of its derivatives, docetaxel, and cabazitaxel.
- Orlistat is a semisynthetic derivative of the natural product lipstatin, which contains β -lactone ring in its structure and is an irreversible inhibitor of pancreatic lipase, an enzyme that breaks down intestinal fat. Without the enzyme, fat in the diet is excreted rather than absorbed by the body, so the drug reduces the absorption of fatty acids from the gastrointestinal tract and is mainly used to treat obesity. It was approved in 1998.
- Paclitaxel is a mitotic inhibitor used in cancer chemotherapy. In 1967, Monroe E. Wall and Mansukh C. Wani isolated the compound from the bark of the Pacific yew tree (Taxus brevifolia) and named it taxol. It was later discovered that taxol was synthesized by endophytic fungi from bark. Paclitaxel drugs have been shown to be effective in the treatment of cancers such as breast, lung and ovarian cancers. The structure-activity relationship of the drug family indicated that oxa-heterocyclobutane was the essential structure for drug activity.
- Docetaxel, which was approved in 1998 and has the same effect as paclitaxel, is an M-phase cycle specific drug, which promotes the polymerization of tubules into stable microtubules and inhibits the aggregation of tubules, resulting in a significant reduction in the number of tubules. And it can destroy the network structure of microtubule. Mainly used for the treatment of gastric cancer, metastatic non-small cell lung cancer, endometrial cancer, esophageal cancer, breast cancer, advanced metastatic breast cancer, and other cancers.
- Cabazitaxel, developed by Sanofi-aventis, was approved for listing in 2010. The anticancer mechanism and characteristics of cabazitaxel are similar to docetaxel, which belongs to anti-microtubule drugs. At present, it is mainly used as a second-line drug in the treatment of prostate cancer, hormone-refractory prostate cancer.
Reference
1. Kaur, N., & Kishore, D. (2014). Solid-phase synthetic approach toward the synthesis of oxygen-containing heterocycles. Synthetic Communications, 44(8), 1019-1042.
2. Sperry, J. B., & Wright, D. L. (2005). Furans, thiophenes and related heterocycles in drug discovery. Current opinion in drug discovery & development, 8(6), 723-740.
eplerenone trilostane picrotoxin
natamycin mupirocin scopolamine