Reversible Influence of Hemipiperazine Photochromism on the Early Development of Zebrafish Embryo

Abstract

This study explores the potential of controlling organismal development with light by using reversible photomodulation of activity in bioactive compounds. Specifically, our research focuses on plinabulin 1, an inhibitor of tubulin dynamics that contains a photochromic motif called hemipiperazine. The two isomeric forms, Z‐1 and E‐1, can partially interconvert with light, yet show remarkable thermal stability in darkness. The Z‐isomer exhibits higher cytotoxicity due to stronger binding to α‐tubulin's colchicine site. The less toxic E‐1 form, considered a "pro‐drug", can be isolated in vitro and stored. Upon activation by blue or cyan light, it predominantly generates the more toxic Z‐1 form. Here we demonstrate that 1 can effectively photomodulate epiboly, a critical microtubule‐dependent cell movement during gastrulation in zebrafish embryos. This research highlights the potential of photomodulation for precise and reversible control of cellular activities and organismal development.

A photo-SAR study of photoswitchable azobenzene tubulin-inhibiting antimitotics identifying a general method for near-quantitative photocontrol

“…In brief however, for photoswitchability of bioactivity, the B ring tolerates small low-polarity groups at the metaposition (active bromo 8 but lower-potency alkoxy 9/10, inactive carboxylate 12); ortho-substituents are disfavoured although still have activity (6 vs 7); and if small, double substitution is allowed (difluoro 16). Matching this, larger rings replacing the phenyl system that were reported for stilbenes [34][35][36][37] were not tolerated in the azobenzenes (19)(20)(21); so their alluring red-shifted photoresponse (Fig 2c ) could not be harnessed. The A ring also tolerates small low-polarity ortho-substituents (22,23); but neither isosteric nor smaller meta groups are tolerated if they are polar (24)(25)(26).…”

“…Azobenzene-based "PSTs" that are structural analogues of combretastatin A-4 are the bestdeveloped platform for reversibly switchable tubulin polymerisation inhibitors. PSTs can be reversibly photoswitched between their bioinactive trans and their up to >100-fold more potent cis isomers, 18 with excellent photostability, by low intensity near-UV and visible light: a combination of features that out-performs almost 19 all other photoresponsive MT inhibitors 20 . In biology, PSTs can photocontrol MT architecture, dynamics, and many MT-dependent processes in living cells with excellent spatiotemporal precision.…”