Insights into Newly Approved Drugs from a Medicinal Chemistry Perspective.

The development of new drugs is becoming notably harder each decade. To overcome the present pitfalls in the drug development pipeline, such as those related to potency, selectivity, or absorption, distribution, metabolism, excretion and toxicity properties, medicinal chemistry strategies need to be in continuous evolution and need to become even more multidisciplinary. In this review, we present how structure-based, ligand-based, and fragment-based drug design (SBDD, LBDD, and FBDD, respectively) and their respective techniques were used for the design and optimization of successful cases of New Molecular Entities (NMEs) approved by the Food and Drug Administration (FDA).

Inibidores de Desmetilase Lisina-Específica 1 (LSD1) como candidatos a agentes antineoplásicos / Lysine-Specif Demethylase 1 (LSD1) inhibitors as candidates for antineoplastic agents

O câncer é uma das principais causas de morte no mundo sendo, atualmente, a segunda principal causa de morte, perdendo apenas para as doenças cardiovasculares, tornando-se um grande desafio para as autoridades de saúde pública. No Brasil são estimados 625000 novos casos desta enfermidade para o triênio de 2020-2022. Nesse cenário, vários alvos epigenéticos são considerados alternativas no desenvolvimento de inibidores para a terapia do câncer devido serem identificados e relacionados com a carcinogênese, incluindo modificações no perfil de metilação do DNA e modificações de histonas como a metilação, acetilação e fosforilação. Dentre estas modificações, a metilação de histonas é regulada reversivelmente por histonas metiltransferases e desmetilases. A enzima desmetilase lisina-específica 1 (LSD1) foi a primeira histona desmetilase caracterizada e catalisa a remoção de grupos metila das lisinas 4 e 9 da histona H3 (H3K4 e H3K9), utilizando o FAD como cofator. Superexpressa em vários tumores de alto risco e tendo seus níveis correlacionados com a reincidência do tumor durante o tratamento, a LSD1 apresenta papel fundamental na tumorgênese. Portanto, tem sido considerado um alvo biológico promissor no desenvolvimento de novos fármacos para terapêutica contra o câncer. Sendo assim, neste trabalho, a partir de dados de triagem virtual baseado neste alvo biológico, selecionou-se um hit, o qual foi utilizado como protótipo para o planejamento de análogos visando melhorar as características farmacológicas, pois possuem grupos químicos passíveis das mesmas interações com o alvo. Foram sintetizadas 16 moléculas, sendo 7 compostos finais inéditos derivados carboxamídicos e 9 derivados sulfonamídicos. Todos os compostos foram caracterizados por RMN (1H e 13C), espectrometria de massas de alta resolução, espectroscopia de infravermelho, ponto de fusão, polarímetro e a pureza dos compostos foi avaliada por CLAE. Os compostos finais foram submetidos ao ensaio enzimático frente à LSD1, acoplado a Enzima Horseradish Peroxidase (EHP), mostrando que apenas o composto 4g apresentou atividade inibitória de 64% e 57% em 50 µM e 500 µM respectivamente. No ensaio de viabilidade celular na linhagem HEL (linhagem leucêmica) os 16 compostos (4a- 4g, 5a-5d e 6a-6d) apresentaram-se ativos com valores de CI50 na faixa de 5,3 µM a 20,25 µM. Os compostos mais potentes foram os 4e (CI50 = 6,9 µM), 5d (CI50 =5,30 µM) e 6ª (CI50 =6,61 µM), evidenciando que os compostos possuem elevada potência, tornando-se moléculas promissoras em linhagens leucêmicas. Os estudos de ancoramento molecular com a LSD1 sugeriram que a mudança de orientação do composto 4g, permitiu que o grupo benzila da porção benzilamida faça interação com os resíduos PHE560 e TYR807 no bolso hidrofóbico, o que possivelmente acarretou um bloqueio na entrada da cavidade, permitindo a inibição pelo composto

Cancer is one of the leading causes of death in the world and is currently the second leading cause of death, second only to cardiovascular disease, making it a major challenge for public health authorities. In Brazil, approximately, 625000 new cases of this disease are estimated for the 2020-2022 period. In this scenario, several epigentic targets are considered alternatives in the development of inhibitors in cancer therapy, since they are identified and related to carcinogenesis, including changes in the DNA methylation profile and changes in histones such as methylation, acetylation and phosphorylation. Among these modifications, histone methylation is reversibly regulated by histones methyltransferases and demethylases. Lysine-specific demethylase1 (LSD1) was the first histone demethylase characterized and catalyzes the removal of methyl groups from lysines 4 and 9 of histone H3 (H3K4 and H3K9), using FAD as a cofactor. LSD1 has been found to be overexpressed in several high-risk tumors and these levels are correlated with tumor recurrence during treatment. Therefore, it has been considered a promising biological target in the development of new drugs with therapeutic potential against cancer. Thus, in this work, the virtual screening technique based on the biological target was used to discover LSD1 interactions, and then based on the hit found, we propose to synthesize compounds that have chemical groups susceptible to such interactions, seeking to evaluate the enzymatic activity in LSD1 enzyme. Were synthesized 16 molecules, 7 of which are unpublished final compound derived from carboxamides and 9 sulfonamide derivatives. All compounds were characterized by NMR (1H and 13C), high resolution mass spectrometry, infrared spectroscopy, melting point, polarimeter and the purity of the compounds was assessed by CLAE. The final compounds were subjected to enzymatic assays Against LSD1, coupled with enzime Horseradish Peroxidase (HRP), showing that only the 4g compound showed 64% and 57% inhibitory activity in 50 µM and 500 µM respectively. In the cell viability assay in the HEL line (Leukemic line) the 16 compounds (4a-4g, 5a-5d and 6a-6d) were active with IC 50 values in the range of 5.3 µM to 20.25 µM. The most potent compounds were 4e (CI50 = 6.9 µM), 5d (CI50 = 5.30 µM) and 6a (CI50 = 6.61 µM), showing that the compounds have high potency, becoming promising molecules in leukemic lines. Docking studies with LSD1 suggested, that the change in orientation of the 4g compound allows the benzyl group of the benzylamide portion to interact with the PHE560 and TYR807 residues in the hydrophobic pocket, which possibly cause a block in the entrance of the cavity, allowing the inhibition by the compound. Thus, the results obtained indicate that the class of compounds described is likely to continue to be investigated, both in the search for new LSD1 inhibitory hits based on the structure of the 4g compound, how to deepen the studies with 16 compounds of the present work in the performance of more specific tests in leukemic cells, in order to unravel the mechanism of action and possible targets

Alkylphospholipids - a promising class of chemotherapeutic agents with a broad pharmacological spectrum.

PURPOSE: Since when alkylphospholipds (ALPs) were discovered and, even further after miltefosine's approval for the treatment of cutaneous metastasis of breast cancer and leishmaniasis, their activity against many other diseases have been extensively studied. This review aims to provide a summary of the alkylphospholipids' applications investigated so far. RESULTS: The mechanism of action of ALPs is not fully understood, however it is believed that they interfere with lipid homeostasis leading to cell apoptosis. Due to ALPs cytotoxic activity, this class of molecules has shown to be effective against many diseases and conditions. Besides the approval of miltefosine for application in cutaneous metastasis of breast cancer and visceral and cutaneous leishmaniasis, several other analogs have proved efficacy and are promising as less toxic alternatives. ALPs have also shown in vitro and in vivo activity against Trypanosoma spp., amoebae, Tricomonas vaginalis, Schistosoma mansoni, HIV, and some fungi and bacteria species. The use of ALPs for intraocular lens coating is also under investigation. In addition, a clinical trial comparing miltefosine with usual treatments to spontaneous urticaria is also being conducted. CONCLUSIONS: Alkylphospholipids present such a broad pharmacological spectrum that justifies the need for further investigations of the drug class mechanisms of action, as well as the search for new analogs with improved activity and toxicological profiles.