ABSTRACT
L-type Ca2+ channels (LTCCs) play a crucial role in excitation-contraction coupling and release of hormones from secretory cells. They are targets of antihypertensive and antiarrhythmic drugs such as diltiazem. Here, we present a photoswitchable diltiazem, FHU-779, which can be used to reversibly block endogenous LTCCs by light. FHU-779 is as potent as diltiazem and can be used to place pancreatic ß-cell function and cardiac activity under optical control.
Subject(s)
Calcium Channels, L-Type/metabolism , Diltiazem/pharmacology , Fluorescent Dyes/pharmacology , Heart/drug effects , Insulin-Secreting Cells/drug effects , Optical Imaging , Calcium Channels, L-Type/chemistry , Diltiazem/chemistry , Fluorescent Dyes/chemistry , Humans , Insulin-Secreting Cells/metabolism , Light , Photochemical ProcessesABSTRACT
Astellatol and nitidasin belong to a subset of sesterterpenoids that share a sterically encumbered trans-hydrindane motif with an isopropyl substituent. In addition, these natural products feature intriguing polycyclic ring systems, posing significant challenges for chemical synthesis. Herein, the evolution of our stereoselective strategy for isopropyl trans-hydrindane sesterterpenoids is detailed. These endeavors included the synthesis of several building blocks, enabling studies toward all molecules of this terpenoid subclass, and of advanced intermediates of our initial route toward a biomimetic synthesis of astellatol. These findings provided the basis for a second-generation and a third-generation approach toward astellatol that eventually culminated in the enantioselective total synthesis of (-)-nitidasin. In particular, a series of substrate-controlled transformations to install the ten stereogenic centers of the target molecule was orchestrated and the carbocyclic backbone was forged in a convergent fashion. Furthermore, the progress toward the synthesis of astellatol is disclosed and insights into some observed yet unexpected diastereoselectivities by detailed quantum-mechanical calculations are provided.
Subject(s)
Biological Products/chemical synthesis , Sesquiterpenes/chemical synthesis , Sesterterpenes/chemistry , Biological Products/chemistry , Biomimetics , Molecular Structure , Sesquiterpenes/chemistry , StereoisomerismABSTRACT
Nitidasin is a pentacyclic sesterterpenoid with a rare 5-8-6-5 carbon skeleton that was isolated from the Peruvian folk medicine "Hercampuri". It belongs to a small class of sesterterpenoids that feature an isopropyl trans-hydrindane moiety fused to a variety of other ring systems. As a first installment of our general approach toward these natural products, we report the total synthesis of the title compound. Our stereoselective, convergent route involves the addition of a complex alkenyl lithium compound to a trans-hydrindanone, followed by chemoselective epoxidation, ring-closing olefin metathesis, and redox adjustment.
Subject(s)
Alkenes/chemistry , Sesterterpenes/chemical synthesis , Biological Products/chemical synthesis , Biological Products/chemistry , Catalysis , Cyclization , Molecular Structure , Sesterterpenes/chemistry , StereoisomerismSubject(s)
Aniline Compounds/chemistry , Potassium Channel Blockers/chemical synthesis , Quaternary Ammonium Compounds/chemistry , Voltage-Gated Sodium Channel Blockers/chemical synthesis , Animals , Humans , Light , Mice , Models, Molecular , Patch-Clamp Techniques , Photochemical Processes , Potassium Channel Blockers/pharmacology , Shaker Superfamily of Potassium Channels/antagonists & inhibitors , Shaker Superfamily of Potassium Channels/metabolism , Voltage-Gated Sodium Channel Blockers/pharmacology , Voltage-Gated Sodium Channels/metabolismABSTRACT
Photochromic channel blockers provide a conceptually simple and convenient way to modulate neuronal activity with light. We have recently described a family of azobenzenes that function as tonic blockers of K(v) channels but require UV-A light to unblock and need to be actively switched by toggling between two different wavelengths. We now introduce red-shifted compounds that fully operate in the visible region of the spectrum and quickly turn themselves off in the dark. Furthermore, we have developed a version that does not block effectively in the dark-adapted state, can be switched to a blocking state with blue light, and reverts to the inactive state automatically. Photochromic blockers of this type could be useful for the photopharmacological control of neuronal activity under mild conditions.