Pre-clinical evaluation of a novel class of anti-cancer agents, the Pyrrolo-1, 5-benzoxazepines.

Abstract

Microtubules are currently ranked one of the most validated targets for chemotherapy; with clinical use of microtubule targeting agents (MTAs) extending beyond half a century. Recent research has focused on the development of novel MTAs to combat drug resistance and drug associated toxicities. Of particular interest are compounds structurally different to those currently used within the clinic. The pyrrolo-1, 5-benzoxazepines (PBOXs) are a structurally distinct novel group of anti-cancer agents, some of which target tubulin. Herein, we review the chemistry, mechanism of action, preclinical development of the PBOXs and comparisons with clinically relevant chemotherapeutics. The PBOXs induce a range of cellular responses including; cell cycle arrest, apoptosis, autophagy, anti-vascular and anti-angiogenic effects. The apoptotic potential of the PBOXs extends across a wide spectrum of cancer-derived cell lines, by targeting tubulin and multiple molecular pathways frequently deregulated in human cancers. Extensive experimental data suggest that combining the PBOXs with established chemotherapeutics or radiation is therapeutically advantageous. Pre-clinical highlights of the PBOXs include; cancer specificity and improved therapeutic efficacy as compared to some current first line therapeutics.

1,5‐Benzoxazepines as a unique and potent scaffold for activity drugs: A review

“…This group of compounds interacts with the cancer cells of the five most common cancers: breast, prostate, stomach, colon, and lung. [35] Among the set of PBOX derivatives, the PBOX-6 (31) and PBOX-15 (32) derivatives are worth mentioning (Scheme 8). All the aforementioned compounds were tested for their action on prostate cancer cells.…”

Structure-activity relationships, biological evaluation and structural studies of novel pyrrolonaphthoxazepines as antitumor agents

“…This latter mechanism could contribute to their anticancer activity [12][13][14][15]. Following our interest in the field [16][17][18], in this scenario, pyrrolo-1,5-benzoxazepines, typified by the 4acetoxy-5-(1-naphthyl) naphtho [2,3-b]pyrrolo [2,1-d] [1,4]oxazepine (PNOX, Table 1) [17,[19][20][21][22][23][24][25][26]. With the aim of further improving the class of benzoxazepine anticancers (antitumor potency and drug-like properties) and to fully elucidate their mechanism of action, we extended our studies by further decorating and/or modifying the original scaffold at different levels [27].…”

A Synthetic Overview of Benzoxazines and Benzoxazepines as Anticancer Agents

“…[20] Benzoxazepine groups have been identified to bind with microtubule assembly leading to exhibit anticancer activity. [21] Benzoxazepine derivatives are effective medicinally potent agents, considered lead molecules for future drug development, [22] like orexin receptor antagonists (Youssef et al 1996, [23] Bajaj et al 2004, [24] Kamei et al 2006, [25] Ai et al 2010, [26] Gijsen et al 2010, [27] Greene et al 2016, [28] ) have attracted vast attention of medicinal chemistry researchers. Within several benzoxazepine isomers, 1,4-and 1,5-benzoxazepine analogues are important due to their profound biological activities.…”