A new chemical series was identified via high-throughput screening as having antiproliferative activity on DU-145 human prostate carcinoma cell line (hit compound potency - 2.9 microM). Medicinal chemistry optimization of two peripheral diversity vectors of the hit molecule, independently, led to SAR generalizations and identification of the 'best' moieties. The latter were merged in a single compound that exhibited an over 100-fold better potency than the hit compound. For the most potent compounds it was confirmed that the observed antiproliferative potency was not associated with the compounds' non-specific cytotoxicity.

Spirocyclic 1-oxa-9-azaspiro[5.5]undecan-4-amine scaffold was explored as a basis for the design of potential inhibitors of soluble epoxide hydrolase (sEH). Synthesis and testing of the initial SAR-probing library followed by biochemical testing against sEH allowed nominating a racemic lead compound (±)-22. The latter showed remarkable (> 0.5 mM) solubility in aqueous phosphate buffer solution, unusually low (for sEH inhibitors) lipophilicity as confirmed by experimentally determined logD of 0.99, and an excellent oral bioavailability in mice (as well as other pharmacokinetic characteristics). Individual enantiomer profiling revealed that the inhibitory potency primarily resided with the dextrorotatory eutomer (+)-22 (IC 4.99 ± 0.18 nM). For the latter, a crystal structure of its complex with a C-terminal domain of sEH was obtained and resolved. These data fully validate (+)-22 as a new non-racemic advanced lead compound for further development as a potential therapeutic agent for use in such areas as cardiovascular disease, inflammation and pain.

A four-center, three-component Ugi-type reaction of a variety of keto acids, Boc-or Cbz-protected hydrazine, and isocyanides offers a simple and high-yielding access to cyclic products containing an N-aminolactam unit. The latter are shown to form consistently an intramolecular hydrogen bond leading to a -turn-like secondary structure. The possibility of integrating such N-aminolactam units (without disruption of the folded structure) into pseudotripeptide fragments is demonstrated.The successful use of keto (as well as aldehydo) carboxylic acids as bifunctional inputs for isocyanide-based multicomponent reactions (IMCR) was demonstrated by Harrimann 1 and Ugi. 2 This four-center, three-component process was found to provide a simple and efficient (as well as atom-economical) entry into novel dipeptoid lactam structures. The strategy has been aggressively exploited to give rise to a wide variety of novel small-and medium-size lactamtype heterocyclic scaffolds 3 and validated, in general, the use of bifunctional reagents in IMCR as a source of significant product diversity. 4

We synthesized two novel ultra low bandgap donor-acceptor (D-A) copolymers (E(g) ≤ 1.2 eV), containing the thiadiazoloquinoxaline unit as the main electron accepting unit (A) and benzodithiophene (BDT) and dithienosilole (DTS) as different donor units (D), denoted as P1 and P2, respectively, using the cross-coupling Stille reaction. The copolymers possess light absorption ranging from UV (350 nm) to near-IR (1300 nm) with optical bandgaps of 1.16 eV and 1.08 eV, respectively. Quantum-chemical calculations and experimental data were compared for proposing a more detailed concept for the optical and electronic properties of these copolymers which can be used as donors for polymer solar cells (PSCs). The PSCs based on optimized P1:PC71BM and P2:PC71BM showed overall power conversion efficiencies (PCEs) of 4.32% and 3.48%, respectively. Although P2 possesses a broad absorption coverage of up to 1300 nm, the lower PCE may be attributed to the low J(sc), due to the poor driving force for exciton dissociation, since the LUMO offset with PC71BM is less than 0.3 eV. The PCE has been significantly increased to 7.27% and 6.68% for solvent vapor annealing (SVA) treated P1:PC71BM and P2:PC71BM active layers, respectively. This improvement arises from the appropriate nanoscale morphology and an increase in hole mobility, induced by the SVA treatment of the active layers.

Substantial development has been made in nonfullerene small molecule acceptors (NFSMAs) that has resulted in a significant increase in the power conversion efficiency (PCE) of nonfullerene‐based polymer solar cells (PSCs). In order to achieve better compatibility with narrow‐bandgap nonfullerene small molecule acceptors, it is important to design the conjugated polymers with a wide bandgap that has suitable molecular orbital energy levels. Here two donor–acceptor (D–A)‐conjugated copolymers are designed and synthesized with the same thienyl‐substituted benzodithiophene and different acceptors, i.e., poly{(4,8‐bis(5‐(2‐ethylhexyl)thiophen‐2‐yl)benzo[1,2‐b:4,5‐b′]dithiophene‐2,6‐diyl)‐alt‐(1,3‐bis(2‐octyldodecyl)‐1,3‐dihydro‐2H‐dithieno[3′,2′:3,4;2″,3″:5,6]benzo[1,2‐d]imidazol‐2‐one‐5,8‐diyl)} (DTBIA, P1) and poly{(4,8‐bis(5‐(2‐ethylhexyl)thiophen‐2‐yl)benzo[1,2‐b:4,5‐b′]dithiophene‐2,6‐diyl)‐alt‐(2‐(5‐(3‐octyltridecyl)thiophen‐2‐yl)dithieno[3′,2′:3,4;2″,3″:5,6]benzo[1,2‐d]thiazole‐5,8‐diyl)} (TDTBTA, P2) (and their optical and electrochemical properties are investigated). Both P1 and P2 exhibit similar deeper highest occupied molecular orbital energy level and different lowest unoccupied molecular orbital energy level. Both the copolymers have complementary absorption with a well‐known nonfullerene acceptor ITIC‐F. When blended with a narrow‐bandgap acceptor ITIC‐F, the PSCs based on P1 show a power conversion efficiency of 11.18% with a large open‐circuit voltage of 0.96 V, a Jsc of 16.89 mA cm−2, and a fill factor (FF) of 0.69, which is larger than that for P2 counterpart (PCE = 9.32%, Jsc = 15.88 mA cm−2, Voc = 0.91 V, and FF = 0.645). Moreover, the energy losses for the PSCs based on P1 and P2 are 0.54 and 0.59 eV, respectively. Compared to P2, the P1‐based PSCs show high values of incident photon to current conversion efficiency (IPCE) in the shorter‐wavelength region (absorption of donor copolymer), more balanced hole and electron mobilities, and favorable phase separation with compact π–π stacking distance.

Two regioregular P1 and random P2 copolymers were synthesized and examined as electron donors in BHJ solar cells. The high PCE achieved of 7.66% for P1 is attributed to increased hole mobility.

S y n t h e s i s o f a -A m i n o P h o s p h o n a t e s D e r i v e d f r o m F o r m y l p o r p h y r i n sAbstract: The first synthesis of a-amino phosphonates comprising porphyrin core was accomplished. Three methods of obtaining aamino phosphonates 5-8 were compared. Conventional heating of formylporphyrins 1-4 with t-BuNH 2 and (EtO) 2 P(O)H in various solvents was ultimately unsuccessful for preparing 5-8 whereas the use of microwave irradiation made it possible to obtain 5-8 in good yields. Regioselective preparation of 5-8 in excellent yields was achieved by combining microwave-assisting conditions and catalysis with CdI 2 . Efficient synthetic procedures of obtaining formylporphyrins 3,4 in large scale were also proposed.Extensive substituent manipulations on porphyrins derived from naturally occurring tetrapyrroles (e.g. heme and chlorocruoroheme) produce a number of phototherapeutic agents efficiently utilized in diverse medical fields including ophthalmology, oncology, gynecology, dermatology, urology, cardiology and immunology. 1-4 The method allowing tetrapyrroles to be used as photosensitizers (PSs) is called photodynamic therapy (PDT). Due to the basic concept of PDT, the combination of two therapeutic agents, a PS and light, which have low toxicity by themselves and being combined in the presence of oxygen lead to ultimate tissue destruction. [1][2][3][4] In order to construct porphyrin-based PSs capable of accumulating selectively in neoplastic (e.g. tumor) tissues a variety of synthetic approaches were elaborated. 1,2 Promising results were achieved by introducing pharmacophor units (e.g. alkoxy-, amino-, a-amino acid residues) into the side-chain positions of porphyrins. 1,2,5 An intriguing class of biologically active compounds are a-amino phosphonates. Due to their structural analogy with a-amino acids and transition state mimicking of peptides, a-amino phosphonates act as potent antibiotics, 6 peptide mimics, 6,7 enzyme inhibitors 6,8 and pharmacological agents. 9With the aim of combining in one molecule phototherapeutic potential of porphyrins and unique biological activity of a-amino phosphonates, we report the first synthesis of a-amino phosphonates comprising porphyrin moiety. It is well documented 10-14 that heterocyclic a-amino phosphonates could be efficiently prepared by the addition of phosphites to aldimine, generated from the corresponding amines and heterocyclic aldehydes. Although there is a broad variety of formylporphyrins derived from natural tetrapyrrols, 2,15 we chose to utilize namely 1-4 15,16 as aldehyde components since formyl group of 1-4 was reported to be an optimum site for designing potent pharmacological agents. 1,2,17-20 (EtO) 2 P(O)H and t-BuNH 2 were employed because they have been successfully used in obtaining various a-amino phosphonates and their motif could be easily detected by NMR. 21-23 Thus, this paper describes the synthesis of a-amino phosphonates 5-8 and synthetic approach to them is shortly depicted in Scheme 1.Our synthesis began from protopo...

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