| 1. |
- Engqvist, Robert
(författare)
-
Syntheses of some tri- and tetracyclic heterocycles containing an indole moiety
- 2004
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis deals with the development of new synthetic methods leading to fused tri- and tetracyclic heterocycles, many of which have interesting biological activity such as antiviral and DNA intercalating properties. The reactions between isatins and 2-aminobenzylamine in acetic acid can give, depending on the conditions, either complex spirooxindoles or indolo[3,2-c]quinolin-6-ones. Proposed mechanisms are presented (involving a simpler form of spirooxindoles). These spirooxindoles can easily be obtained from isatins and 2-aminobenzylamine in methanol (Paper I). The previously unknown, but incorrectly claimed, linear isomer of indolo[3,2-c]quinolin-6one, i.e. indolo[2,3-b]quinolin-11-one, has been prepared for the first time by thermal (260 degrees C) cyclization of methyl 2 -phenylamino-indole-3 -carboxylate, which was in turn prepared in two steps from methyl indole-3 -carboxylate. The benzothiopyrano[2,3-b]indol-11-one and benzopyrano[2,3-b]indol-11-one could be prepared similarly (Papers I and II). Suitable 2-chloro-3-formylindoles have been used for the preparation of the alkaloids neocryptolepine, thienodolin and derivatives thereof (Papers III and IV). Finally, synthetic work towards potential metabolites of the lead compound B-220 is presented. We have described a method for reduction of the biologically interesting indolo[2,3b)quinoxalines with zinc, which are subsequently trapped with an appropriate anhydride to provide the corresponding mono or diacylated 5,1 1-dihydroindolo[2,3b]quinoxalines in good yields (paper V). Synthesis of hydroxy derivatives of B-220 can be effected from the appropriate methoxyisatins. Futher derivatives like the vinyl-, Nmethylaminoethyl- and Noxido derivatives of B-220 have also been synthesised.
|
|
| 2. |
- Devaraj, Karthik
(författare)
-
Ruthenium-catalyzed C-H Functionalization of (Hetero)arenes
- 2017
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis concerned about the Ru-catalyzed C-H functionalizations on the synthesis of 2-arylindole unit, silylation of heteroarenes and preparation of aryne precursor.In the first project, we developed the Ru-catalyzed C2-H arylation of N-(2-pyrimidyl) indoles and pyrroles with nucleophilic arylboronic acids under oxidative conditions. Wide variety of arylboronic acids afforded the desired product in excellent yield regardless of the substituents or functional group electronic nature. Electron-rich heteroarenes are well suited for this method than electron-poor heteroarenes. Halides such as bromide and iodide also survived, further derivatisation of the halide is shown by Heck alkenylation. In order to find catalytic on-cycle intermediate extensive mechanistic experiments have been carried out by preparing presumed ruthenacyclic complexes and C-H/D exchange reactions. It suggested that para-cymene ligand is not present in the catalytic on-cycle intermediate and we suspect that metalation occurs with electrophilic ruthenium center via SEAr mechanism.In the second project, we developed the Ru-catalyzed silylation of gramine, tryptamine and their congeners using silanes as coupling partner. The transformation worked well with many different silanes. Regarding directing group, nitrogen atom containing directing groups are more favoured than the oxygen containing directing groups. Wide range of gramines and tryptamines also yielded the desired product in poor to excellent yield. At higher temperature, albeit in low yield, undirected silylation occurred. In order to get some insights about the reaction pathway of the silylation C-H/D exchange experiments were performed, and it revealed the possibility of C4-H activation of gramines by an electron rich metal- Si-H/D experiments showed Si-H activation by Ru is easy.In the final project, we presented the closely related aryne precursors from arylboronic acids via Ru-catalyzed C-H silylation of arylboronates and their selective oxidation. Worthy of note, the aryne capture products obtained from arylboronic acids in a single purification.
|
|
| 3. |
- Gising, Johan, 1981-
(författare)
-
Design and Synthesis of Enzyme Inhibitors Against Infectious Diseases : Targeting Hepatitis C Virus NS3 Protease and Mycobacterium tuberculosis Ribonucleotide Reductase
- 2012
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Infectious diseases, including hepatitis C and tuberculosis, claim the lives of over 15 million people each year. Hepatitis C is caused by the hepatitis C virus (HCV) which infects the liver and can ultimately result in liver transplantation. HCV is very adaptive as a result of its high mutation rate. Thus, there is a potential high risk for the development of drug resistance and also a possible cross-resistance due to a structural similarity between many of the HCV NS3 protease inhibitors currently in clinical trial and on the market, that all are based on a P2-proline or a proline mimic. Thus, part of the research behind this thesis was to explore a new structural P3-P2 unit for the NS3 protease inhibitors, a 2(1H)-pyrazinone moiety. A microwave-assisted protocol was developed, and the 2(1H)-pyrazinone core was synthesized in only 2 × 10 min. A series of optimization steps resulted in several submicromolar 2(1H)-pyrazinone-containing NS3 protease inhibitors that performed well against drug-resistant NS3 protease variants. The key modifications were: exchanging the unstable carbamate P3 capping group for a stable urea functionality, transferring the P2 group from the amino acid residue to the pyrazinone ring and elongating the substituent, and using an aromatic acyl sulfonamide in the P1-P1' position.The causative agent of tuberculosis is Mycobacterium tuberculosis (Mtb), which currently infects one third of the world's population. No new TB drugs have been approved in nearly 50 years and drug resistance has been observed for all of the current first-line drugs. Because of the importance of identifying novel drug targets, the ribonucleotide reductase (RNR) enzyme was investigated. The RNR enzyme consists of two R1 and two R2 subunits and is essential for Mtb replication. Starting from hits identified in a virtual screening program, a small library of low molecular weight inhibitors of the association between the R1 and R2 subunits was designed and synthesized. The compounds with the strongest affinity for the R1 subunit of RNR were further evaluated in an orthogonal activity assay. Two RNR inhibitors with promising antimycobacterial effects were identified, which can serve as leads in the further optimization of this class of compounds.
|
|
