Natural Product-Derived Spirooxindole Fragments Serve as Privileged Substructures for Discovery of New Anticancer Agents

Abstract

The utility of natural products for identifying anticancer agents has been highly pursued in the last decades and over 100 drug molecules in clinic are natural products or natural product-derived compounds. Natural products are believed to be able to cover unexplored chemical space that is normally not occupied by commercially available molecule libraries. However, the low abundance and synthetic intractability of natural products have limited their applications in drug discovery. Recently, the identification of biologically relevant fragments derived from biologically validated natural products has been recognized as a powerful strategy in searching new biological probes and drugs. The spirocyclic oxindoles, as privileged structural scaffolds, have shown their potential in designing new drugs. Several anticancer drug candidates such as SAR405838, RO8994, CFI-400945 and their bioisosteres are undergoing clinical trials or preclinical studies. To highlight the significant progress, we focus on illustrating the discovery of SAR405838, RO8994, CFI-400945 and their bioisosteres for cancer therapy using substructure-based strategies and discussing modes of action, binding models and preclinical data.

Structurally novel steroidal spirooxindole by241 potently inhibits tumor growth mainly through ROS-mediated mechanisms

“…From our in-house steroid library, one structurally novel steroidal derivative (named by241 , Fig. 1 ) stood out with favorable anticancer efficacy, featuring a spiro-cyclic oxindole scaffold attached to the steroid nucleus 24 25 26 . In the present study, we would like to report the anticancer properties of this shortlisted compound and its possible mechanisms of action.…”

Recent Advances on the Synthesis and Antitumor Evaluation of Exonuclear Heterosteroids

“…螺吲哚酮类化 合物因其新颖的 3D 骨架结构和广泛的生物学活性如抗 HIV [10] 、抗肿瘤 [11,12] 、抗结核 [13] 、抗疟疾 [14] 等得到了广 泛关注. 在抗肿瘤药物设计方面 [12,15] , 螺吲哚酮类化合 物 RO8994 [16] 和 SAR405838 [17] 作为 MDM2 抑制剂, 其 分别处在临床前和 I 期临床试验中, 用于肿瘤的治疗;…”

The Development of Biologically Important Spirooxindoles as New Antimicrobial Agents

“…Spirooxindole (Highlighted in red in Fig. 1) containing compounds have exhibited diverse biological properties, such as anticancer [16][17][18][19][20][21], antimicrobial [22,23], antivirus [24], etc. Representative examples are NITD609 (also known as Cipargamin) [25], CFI-400945 (the first PLK4 inhibitor) [26,27], SAR405838 (MDM2 inhibitor) [28,29] and APG-115 (MDM2 inhibitor) Fig.…”