Metal based therapeutics are a precious class of drugs in oncology research that include examples of theranostic drugs, which are active in both diagnostic, specifically imaging, and therapeutics applications. Ruthenium compounds have shown selective bioactivity and the ability to overcome the resistance that platinum-based therapeutics face, making them effective oncotherapeutic competitors in rational drug invention approaches. The development of antineoplastic ruthenium therapeutics is of particular interest because ruthenium containing complexes NAMI-A, KP1019, and KP1339 entered clinical trials and DW1/2 is in preclinical levels. The very robust, conformationally rigid organometallic Ru(II) compound DW1/2 is a protein kinase inhibitor and presents new Ru(II) compound designs as anticancer agents. Over the recent years, numerous strategies have been used to encapsulate Ru(II) derived compounds in a nanomaterial system, improving their targeting and delivery into neoplastic cells. A new photodynamic therapy based Ru(II) therapeutic, TLD-1433, has also entered clinical trials. Ru(II)-based compounds can also be photosensitizers for photodynamic therapy, which has proven to be an effective new, alternative, and noninvasive oncotherapy modality.

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This manuscript describes a novel class of N-acylhydrazone (NAH) derivatives that act as histone deacetylase (HDAC) 6/8 dual inhibitors and were designed from the structure of trichostatin A (1). Para-substituted phenyl-hydroxamic acids presented a more potent inhibition of HDAC6/8 than their meta analogs. In addition, the effect of compounds (E)-4-((2-(4-(dimethylamino)benzoyl)hydrazono)methyl)-N-hydroxybenzamide (3c) and (E)-4-((2-(4-(dimethylamino)benzoyl)-2-methylhydrazono)methyl)-N-hydroxybenzamide (3f) on the acetylation of α-tubulin revealed an increased level of acetylation. These two compounds also affected cell migration, indicating their inhibition of HDAC6. An analysis of the antiproliferative activity of these compounds, which presented the most potent activity, showed that compound 3c induced cell cycle arrest and 3g induced apoptosis through caspase 3/7 activation. These results suggest HDAC6/8 as a potential target of future molecular therapies for cancer.

Duvelisib (Copiktra®) is a dual inhibitor of phosphoinositide 3-kinases (PI3Kδ and PI3Kγ). In 2018, duvelisib was first approved by the Food and Drug Administration (FDA) for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukaemia (CLL)/ small lymphocytic lymphoma (SLL) after at least two prior therapies. Duvelisib has also been approved under accelerated track for relapsed or refractory follicular lymphoma (FL) after at least two prior systemic therapies. In this review, we provide a series of information about duvelisib, such as the development of clinical trials for LLC/SLL and FL and the steps used for its synthesis.

Despite the applicability of histone deacetylase inhibitors (HDACis) for cancer treatment, several works in the literature have shown that these inhibitors can be used in several other diseases, such as neurodegenerative diseases (NDs). This review begins by discussing the signaling pathways of HDACs, focused on the context of NDs, presenting a discussion about the pharmacophoric features of HDACis and crystal structure analysis and discussing interesting case studies from the literature about the development of HDACis. Additionally, a discussion about the consequences of isoform-selective inhibition vs pan-HDACis on neurotoxic effects and clinical trial investigations of HDACis for NDs is also presented.

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Histone deacetylase 6 (HDAC6) catalyses the removal of acetyl groups from the lysine residues of a series of non-histone proteins, e.g., α-tubulin, Hsp90 and cortactin. HDAC6 is a unique deacetylase enzyme that is related to various processes that may be important in oncological, immunological and neurological fields, which makes the study of selective inhibitors extremely important to understand the function of this enzyme and to validate HDAC6 as a drug target through the development of clinical candidates. Therefore, this review describes the structure-activity and structureselectivity relationships of HDAC6 inhibitors, which were divided into two main classes, bulky and lipophilic cap groups and inhibitors with phenyl linkers.

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