Novel Nitrogen-Enriched Oridonin Analogues with Thiazole-Fused A-Ring: Protecting Group-Free Synthesis, Enhanced Anticancer Profile, and Improved Aqueous Solubility

Abstract

Oridonin (1), a complex ent-kaurane diterpenoid isolated from the traditional Chinese herb Isodon rubescens, has demonstrated great potential in the treatment of various human cancers due to its unique and safe anticancer pharmacological profile. Nevertheless, the clinical development of oridonin for cancer therapy has been hampered by its relatively moderate potency, limited aqueous solubility and poor bioavailability. Herein, we report the concise synthesis of a series of novel nitrogen-enriched oridonin derivatives with thiazole-fused A-ring through an efficient protecting group-free synthetic strategy. Most of them including compounds 7-11, 13 and 14 exhibited potent antiproliferative effects against breast, pancreatic and prostate cancer cells with low micromolar to submicromolar IC50 values, as well as markedly enhanced aqueous solubility. These new analogs obtained by rationally modifying the natural product have been demonstrated not only to significantly induce the apoptosis and suppress growth of triple-negative MDA-MB-231 breast cancer both in vitro and in vivo, but also effective against drug-resistant ER-positive MCF-7 clones.

Discovery and development of natural product oridonin-inspired anticancer agents

“…4) [50]. Most of these compounds exhibit improved cytotoxicity (EC 50 = 0.93–21.70 μ M for B16 murine melanoma cells) and aqueous solubility (> 50 mg/mL) in comparison with oridonin (EC 50 = 26.15 μ M for B16 murine melanoma cells [50]; aqueous solubility 1.29 mg/mL [51]). Compounds 3 – 5 bearing an acetate at the C-1 position display an inhibitory activity more potent than the corresponding compounds 6 – 9 bearing a propylsulfonyl or carbonyl group at the same position.…”

“…Over the past several years, our group explored new scaffold constructions around the A-ring system of oridonin [51, 65–67]. The aromatic thiazole heterocycle represents an important anticancer pharmacophore that exists in bioactive natural products and FDA approved drugs, such as epothilone B and ixabepilone [68–70].…”

“…The aqueous solubility of compound 28 has been significantly improved with a saturated concentration of 42.4 mg/mL, which is approximately 32-fold higher than that of oridonin (1.29 mg/mL). Moreover, compound 28 significantly suppresses MDA-MB-231 xenograft tumor growth in vivo at a dosage of 5 mg/kg (ip, tumor growth inhibition > 66%), while oridonin at the same dosage displays no significant efficacy in the same animal model [51]. …”

Oridonin triggers apoptosis in colorectal carcinoma cells and suppression of microRNA-32 expression augments oridonin-mediated apoptotic effects

“…Therefore, some researchers tried to enhance its oral bioavailability by increasing the dissolution rate of the drug from its dosage form [38]. In addition, some novel 1-O-and 14-O-derivatives of oridonin or nitrogenenrich oridonin analogs were found to exhibit stronger anti-tumor activity than its parent compound [39,40]. In this study, oridonin administration through intraperitoneal injection strongly inhibited tumor growth in nude mice.…”

Formulation and evaluation of biodegradable nanoparticles for the oral delivery of fenretinide

“…The National Institute of Health has estimated that it has screened over 80,000 compounds since 1990 [2]. The screenings have focused on compounds intended to treat specific cancers, such as lung [3], breast [4], and prostate cancer [5], and they have focused on general anti-tumor effects. While these tests reveal anti-tumor effects, in most cases they do not reveal whether the compound may be useful for treating cancer from a practical standpoint.…”