Design, synthesis and biological evaluation of small-molecules targeting the Mdmx-p53 interaction and the Atad2 bromodomain for cancer therapy

Phd ThesisIn this thesis small molecule inhibitors of MDMX-p53 interaction, and ATAD2 bromodomain are investigated. In many human cancers, the function of the tumour suppressor protein p53 is inhibited by the overexpression of MDM2 or MDMX. Modulation of MDM2-p53 and MDMX-p53 interactions is therefore an attractive strategy for anticancer drug discovery. A number of small molecule inhibitors of the MDM2-p53 interaction have been reported to date and several have entered clinical trials. Although MDM2 and MDMX have a high sequence homology, most of the small molecule MDM2 inhibitors show significantly lower binding affinity towards MDMX. A series of 2,4-aminothiazoles including compound 1 with modest inhibitory activity against the MDM2-p53 and MDMX-p53 interactions has been reported. The series was extended to a pyrrole series, which led to the discovery of compound 2 with low micromolar dual inhibition of MDM2/MDMX and structure-activity relationship studies were conducted. An ELISA was used to examine potency against MDM2-p53 and MDMX-p53. Although, the assay gave results in agreement with literature values for some inhibitors of the MDM2-p53 interaction, the potencies of the published dual inhibitors RO-2443 3 and RO-5963 4 were around 1000-fold lower than reported. Therefore, an HTRF assay was developed, which provided IC50 values comparable to the reported values for inhibition of MDM2-p53 and MDMX-p53 by RO-5963. Co-crystallisation experiments, using three different constructs of MDMX, were attempted using 15 compounds. vi Bromodomains are protein modules that function as epigenetic readers of histone lysine acetylation. ATAD2, a bromodomain containing protein, is overexpressed in a wide range of human cancers including breast, lung, prostate, ovarian, liver, osteosarcoma and gastrointestinal carcinomas. Due to the polar and flexible nature of the binding surface, ATAD2 has been considered as a challenging target for ligand discovery. Therefore, very few potent and selective inhibitors of ATAD2 bromodomains have been reported to date. Extensive SAR studies around hit 5 obtained from a fragment screening led to the identification of a sub-millimolar inhibitor 6 of ATAD2 bromodomain. Co-crystal structures of ATAD2 were used to guide compound design and synthesis

Design, synthesis and characterization of organic semiconductors: From eumelanin-inspired organic materials to novel electron acceptors

Eumelanin, the black-brown variety of natural pigment melanin, is a fascinating material owing to its multifunctional physicochemical properties, such as broad-band absorption spectrum, antioxidant and free radical scavenging behavior, strong nonradiative relaxation of photoexcited electronic states and metal chelating properties. Further, biocompatible and biodegradable nature, peculiar physicochemical properties and intrinsic antimicrobial activities make eumelanin a promising material in bioelectronic and biomedical fields. Here, the Eumelanin-inspired indole core has been utilized to synthesize bio-inspired organic semiconductors (OSCs), sensors, and antimicrobials.In the field of organic semiconductors, both p-type and n-type materials are equally important. While p-type OSCs have seen a dramatic rise in performance over the last decade, n-type OSCs, in general, still lag behind p-type OSCs. This lack of high performance n-type OSCs is mainly related to lower stability, difficulties in synthesis and less availability of electron deficient building blocks that can be used for making n-type OSCs. Both types of OSCs with high performance are required in order to fabricate high-performance complementary circuits or p-n junction devices. Thus, there is a critical need for exploration of new building blocks for making novel n-type OSCs with improved electron mobility, material stability both under processing and operational conditions, and ease of synthesis. Benzo[1,2-b:4,5-b0 ]dithiophene-1,1,5,5-tetraoxide (BDTT) has seen less utility as a building block to make n-type OSCs despite it being an electron poor heterocycle with promise for development of n-type materials. Difficulties in functionalizing BDTT via carbon-carbon cross coupling reactions and often in low yield is one likely reason for the lack of utilization of BDTT in OSCs. This dissertation will report the successful functionalization and utilization of BDTT for the synthesis of n-type OSCsIn past few years, organic conductive fibers have emerged as an attractive as well as promising class of materials for realizing non-metallic electrodes for different clinical applications. This is because these materials are biocompatible, better integrated, easier to fabricate, lightweight and have limited magnetic resonance imaging problems compared to the metallic electrodes. This dissertation will highlight novel organic conductive fibers that have been fabricated by a facile, economical, and scalable method by using conductive ink prepared from the two intrinsically conductive materials - poly(3-hexylthiophene) and single walled carbon nanotubes - and these conductive fibers have been utilized as non-metallic electrodes for recording skin surface biological signals

Present status and future prospects to safeguard Nepali citrus industry against Chinese citrus fly (Bactrocera minax Enderlein)

Unlike other Tephrid flies, the Chinese citrus fly (Bactrocera minax Enderlein) is univoltine and oligophagous species strictly restricted to citrus fruits. It has been a serious threat to the citrus industry in China, Bhutan, India and Nepal causing up to 100% of fruit drop before the harvest. Citrus groves, especially tight-skinned cultivars, sweet orange (Citrus sinensis L. Osbeck) in mid-hill districts like Ramechhap, Sindhuli, Dolakha, Kavre, Syangja, Gulmi, etc. have been threatened while in some pockets, lemon, acid lime, and mandarin have vanished due to the Chinese citrus fly (CCF). The driver behind the spread of this invasive pest seems to be poor research works on the phenology of the pest, ill-equipped management practices, flying nature of adult fly and easy movement of infested fruits. Therefore, with reviewing published data, this study aimed to figure out the most appropriate management technology for curbing the CCF and make comprehensive material for safeguarding the citrus industry in the future. Since Area-Wide Integrated Pest Management (AW-IPM) or Area-Wide Control Program (AWCP) was found to be an effective tool to control the CCF, individual practices are crucial to incorporate. Monitoring the pest with the lure of protein hydrolase (PH) and subsequently killing adults with attractive protein baits of 25% hydrolyzed protein + insecticide as lethal dinner is mentioned exceptionally better. In AWCP domestic practice: orchard sanitation is not so effective if the orchards are sloppy while shallow tillage adds less to the natural enemy mechanism of CCF pupae in the soil. Equally, we conclude that Sterile Insect Technology (SIT) is not so economical and the boons of natural enemies, parasitoid and entomo-pathogens against CCF, is yet to be exploited

Resource use efficiency of maize production with and without irrigation system in Kaski, Nepal

The study examined the resource use efficiency of maize production in rainfed and irrigated conditions in Kaski, Nepal. It focused specially on the production function of maize, resource use efficiency and socioeconomic characteristics of the farmers. A well-structured interview schedule was used in this study. Out of the 368 households interviewed, 165 farmers cultivated maize and a total of 157 farmers (59 from irrigated and 98 from rainfed) provided useful data. The data analysis was done by using Microsoft excel and SPSS. Cobb-Douglas production function was used to determine the resource use efficiency of maize production.  Compared to rainfed system, maize productivity in irrigated system was higher despite the use of fewer input implying irrigation. Increase in seed use by 10% increased the yield by 1.9% in case of rainfed system and 0.05% in case of the irrigated system. The major implication for the study is that farmers should make proper utilization of their resources to achieve higher level of resource use efficiency