Wolfgang Kramer

Diastereo- and Enantioselective Synthesis of Pyrrolo[1,4]benzodiazepines through Decarboxylative Photocyclization

Memory of chirality in triplet 1,7-diradicals was detected for the first time and to a remarkably high degree in the decarboxylative photocyclization of the proline derivative of N-phthaloyl anthranilic acid 1 into 2 (X=H: 45 % yield, 86 % ee; X=Cl: 50 % yield, 79 % ee).

Photoinduced decarboxylation reactions. Radical chemistry in water

Intramolecular photodecarboxylation reactions of potassium ω-phthalimido carboxylates in water or mixtures of water and organic solvents (acetone, acetonitrile) were investigated using an incoherent XeCl excimer radiation source emitting at 308 nm. Electron transfer induced intermolecular addition of alkyl carboxylates to phthalimides likewise proceeded efficiently under these conditions. The reactions can be performed in multigram (i.e. 10–30 g product) quantities using easiliy available substrates such as glutamic acid (for the synthesis of 3), leucine (for 8, 9) or simple alkyl carboxylates (for 11). The advantages of this methodology are: clean and high-yielding reactions, solvent and waste minimization, water-based processes and efficient utilization of photons of defined energy.

Photochemistry of phthaloylcysteine, its methyl ester and C-unprotected S-alkyl derivatives☆

Abstract N-Phthaloyl cysteine derivatives 1a-d were photochemically transformed by elimination, decarboxylation, and via electron transfer cyclization to the products 2,3,4 and 6–8. The spin selectivities of singlet and triplet pathways were investigated in acetonitrile and acetone. The excited singlets were prone to elimination and γ-H abstractions (e.g. formation of 5) whereas the triplets cyclized to thiazinoisoindoles. This behaviour can be correlated with the efficiencies of forward and return electron transfer steps versus homolytic hydrogen abstractions as examplified for the cysteine substrate 9.

Characterization of diadzein–hemoglobin binding using optical spectroscopy and molecular dynamics simulations

The present study establishes the effectiveness of natural drug delivery mechanisms and investigates the interactions between drug and its natural carrier. The binding between the isoflavone diadzein (DZN) and the natural carrier hemoglobin (HbA) was studied using optical spectroscopy and molecular dynamics simulations. The inherent fluorescence emission characteristics of DZN along with that of tryptophan (Trp) residues of the protein HbA were exploited to elucidate the binding location and other relevant parameters of the drug inside its delivery vehicle HbA. Stern-Volmer studies at different temperatures indicate that static along with collisional quenching mechanisms are responsible for the quenching of protein fluorescence by the drug. Molecular dynamics and docking studies supported the hydrophobic interactions between ligand and protein, as was observed from spectroscopy. DZN binds between the subunits of HbA, ∼15 Å away from the closest heme group of chain α1, emphasizing the fact that the drug does not interfere with oxygen binding site of HbA.

Structural and Hydrodynamic Analysis of a Novel Drug Delivery Vector: ELP[V5G3A2-150]

The therapeutic potential of elastin-like polypeptide (ELP) conjugated to therapeutic compounds is currently being investigated as an approach to target drugs to solid tumors. ELPs are hydrophobic polymers that are soluble at low temperatures and cooperatively aggregate above a transition temperature (TT), allowing for thermal targeting of covalently attached drugs. They have been shown to cooperatively transition from a disordered structure to a repeating type II β-turn structure, forming a β-spiral above the TT. Here we present biophysical measurements of the structural, thermodynamic, and hydrodynamic properties of a specific ELP being investigated for drug delivery, ELP[V5G3A2-150]. We examine the biophysical properties below and above the TT to understand and predict the therapeutic potential of ELP-drug conjugates. We observed that below the TT, ELP[V5G3A2-150] is soluble, with an extended conformation consisting of both random coil and heterogeneous β structures. Sedimentation velocity experiments indicate that ELP[V5G3A2-150] undergoes weak self-association with increasing temperature, and above the TT the hydrophobic effect drives aggregation entropically. These experiments also reveal a previously unreported temperature-dependent critical concentration (Cc) that resembles a solubility constant. Labeling ELP[V5G3A2-150] with fluorescein lowers the TT by 3.5°C at 20 μM, whereas ELP[V5G3A2-150] dissolution in physiological media (fetal bovine serum) increases the TT by ∼2.2°C.

Stereo- and spinselectivity of primary (singlet) and secondary (triplet) Norrish type II reactions

Abstract The influence of reactive conformation and substitution pattern on the Norrish Type II reactivity and selectivity of singlet-excited phthalimides was investigated. Only the cis-diasteroisomer of the 4-tert-butyl cyclohexylamine derivatives 1 underwent Yang cyclization. The phthaloyl leucine esters 3a and 3b both gave primarily Yang cyclization with subsequent ring expansion. As a secondary photoreaction, 3a gave Norrish II cleavage solely, wheras photolysis of the tert.-butyl ester 3b resulted in a 1:1 mixture of Norrish II cleavage and Yang cyclization product 4 and 5 .

N-Alkoxyheterocycles As Irreversible Photooxidants†

Irreversible photooxidation based on N–O bond fragmentation is demonstrated for N‐methoxyheterocycles in both the singlet and triplet excited state manifolds. The energetic requirements for bond fragmentation are studied in detail. Bond fragmentation in the excited singlet manifold is possible for ππ* singlet states with energies significantly larger than the N–O bond dissociation energy of ca 55 kcal mol−1. For the nπ* triplet states, N–O bond fragmentation does not occur in the excited state for orbital overlap and energetic reasons. Irreversible photooxidation occurs in the singlet states by bond fragmentation followed by electron transfer. Irreversible photooxidation occurs in the triplet states via bimolecular electron transfer to the donor followed by bond fragmentation. Using these two sensitization schemes, donors can be irreversibly oxidized with oxidation potentials ranging from ca 1.6–2.2 V vs SCE. The corresponding N‐ethylheterocycles are characterized as conventional reversible photooxidants in their triplet states. The utility of these sensitizers is demonstrated by irreversibly generating the guanosine radical cation in buffered aqueous solution.

Photocyclization of N,N-phthaloylanthranilic amides coupled to ω-amino acids with increasing chain lengths

Medium-sized heterocyclic ring systems are available via a photo-electron transfer (PET)-induced decarboxylation-cyclization sequence using a triad composed of electronically excited acceptor, linker and electrondonor A*-L-D with target ring sizes varying from 8-16.

Effect of basic cell-penetrating peptides on the structural, thermodynamic, and hydrodynamic properties of a novel drug delivery vector, ELP[V5G3A2-150].

Elastin-like polypeptides (ELPs) are large, nonpolar polypeptides under investigation as components of a novel drug delivery system. ELPs are soluble at low temperatures, but they desolvate and aggregate above a transition temperature (TT). This aggregation is being utilized for targeting systemically delivered ELP–drug conjugates to heated tumors. We previously examined the structural, thermodynamic, and hydrodynamic properties of ELP[V5G3A2-150] to understand its behavior as a therapeutic agent. In this study, we investigate the effect that adding basic cell-penetrating peptides (CPPs) to ELP[V5G3A2-150] has on the polypeptide’s solubility, structure, and aggregation properties. CPPs are known to enhance the uptake of ELP into cultured cells in vitro and into tumor tissue in vivo. Interestingly, the asymmetric addition of basic residues decreased the solubility of ELP[V5G3A2-150], although below the TT we still observed a low level of self-association that increased with temperature. The ΔH of the aggregation process correlates with solubility, suggesting that the basic CPPs stabilize the aggregated state. This is potentially beneficial as the decreased solubility will increase the fraction aggregated and enhance drug delivery efficacy at a heated tumor. Otherwise, the basic CPPs did not significantly alter the biophysical properties of ELP. All constructs were monomeric at low temperatures but self-associate with increasing temperature through an indefinite isodesmic association. This self-association was coupled to a structural transition to type II β-turns. All constructs reversibly aggregated in an endothermic reaction, consistent with a reaction driven by the release of water.