Structure−Activity Relationship Studies of Novel Heteroretinoids:  Induction of Apoptosis in the HL-60 Cell Line by a Novel Isoxazole-Containing Heteroretinoid

Daniele, Simona; Invidiata, Francesco Paolo; Rondanin, Riccardo; Grimaudo, Stefania; Cannizzo, Giuliana; Barbusca, Eleonora; Porretto, Ferdinando; d’Alessandro, Nicola; Tolomeo, Manlio

doi:10.1021/jm991059n

Cited by 50 publications

(26 citation statements)

References 30 publications

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“…The acetylenic function in 21a,b was transformed to isoxazole (compounds 23a,b ) by 1,3-dipolar cycloaddition with a nitrile oxide generated in situ from ethyl chlorooximinoacetate and a base. [14] The intermediates 21c,d were reduced to the aniline derivatives 22a,b , which after treatment with ethyl chloroformate or di- tert -butyl dicarbonate to provide corresponding carbamates, were converted to the isoxazoles 23c–e . Lastly, reaction of 23 with freshly prepared hydroxylamine [15] generated the desired hydroxamic acids 1–5 .…”

Section: Resultsmentioning

confidence: 99%

Identification of HDAC6‐Selective Inhibitors of Low Cancer Cell Cytotoxicity

et al. 2015

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The histone deacetylases (HDACs) occur in 11 different isoforms, and these enzymes regulate the activity of a large number of proteins involved in cancer initiation and progression. The discovery of isoform selective HDAC inhibitors (HDACIs) is desirable, as it is likely that such compounds would avoid some of the undesirable side effects found with the first generation inhibitors. A series of HDACIs previously reported by us were found to display some selectivity for HDAC6 and to induce cell cycle arrest and apoptosis in pancreatic cancer cells. In the present work, we show that structural modification of these isoxazole-based inhibitors leads to high potency and selectivity for HDAC6 over HDAC1-3 and HDAC10, while unexpectedly abolishing their ability to block cell growth. Three inhibitors with lower HDAC6 selectivity inhibit the growth of cell lines BxPC3 and L3.6pl, and they only induce apoptosis in L3.6pl. We conclude that HDAC6 inhibition alone is insufficient for disruption of cell growth, and that some degree of class 1 HDAC inhibition is required. Moreover, the highly selective HDAC6Is reported herein that are weakly cytotoxic may find use in cancer immune system reactivation.

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Section: Resultsmentioning

confidence: 99%

Identification of HDAC6‐Selective Inhibitors of Low Cancer Cell Cytotoxicity

et al. 2015

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“…on the α-carbon can be effectively utilized towards the synthesis of pyrazoles, [25] isoxazoles, [26] triazole [27] and a number of bicyclic or polycondensed heterocycles of pharmaceutical importance. In addition to the above properties, 1,3-diketones are key structural units in many chelating ligands for lanthanide and transition metals.…”

Section: Resultsmentioning

confidence: 99%

A Simple and Efficient Strategy Towards Eleven‐Membered Carbocycles via Novel Synthetic Transformations of Pentafulvenes

et al. 2007

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A novel and versatile method towards the synthesis of eleven-membered carbocycles through a three step reaction sequence from pentafulvenes is described. The [6+3] adduct of pentafulvenes with 3-oxidopyrylium betaine on selective reduction followed by ruthenium catalyzed oxidative cleavage afforded a novel eleven-membered carbocyclic triketone with a bridging ether linkage. The methodology described

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“…They were diluted in appropriate experimental concentrations in tissue medium and protected from light. In each experiment DMSO never exceeded 0.5% and this percentage did not interfere with cell growth and did not induce di erentiation in HL60 cells at 48 and 72 h (Simoni et al, 1999).…”

Section: Drug Preparationmentioning

confidence: 87%

Effects of chemically modified tetracyclines (CMTs) in sensitive, multidrug resistant and apoptosis resistant leukaemia cell lines

Tolomeo

Grimaudo

Milano

et al. 2001

British J Pharmacology

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1 Recently discovered chemically modi®ed tetracyclines (CMTs) have shown in vitro and in vivo anti-proliferative and anti-tumour activities. Here, we evaluated in vitro the anti-proliferative and apoptotic activity of six di erent dedimethylamino chemically modi®ed tetracyclines (CMT-1, CMT-3, CMT-5, CMT-6, CMT-7 and CMT-8) in sensitive and multidrug resistant myeloid leukaemia cells (HL60 and HL60R) in vitro. 2 Three of these compounds (CMT-5, CMT-6, CMT-7) showed low cytotoxic activity both in sensitive and in resistant cells, CMT-3 was endowed with a high anti-proliferative activity only in sensitive cells and was moderately e ective as apoptosis inducing agent, with an activity similar to that shown by doxycycline. On the contrary, CMT-1 and CMT-8 were very e ective as programmed cell death inducing agents. 3 The apoptotic pathway activated by these compounds involved the activation of caspases, especially caspase-9 and, for CMT-1, also the activation of Fas. 4 Interestingly CMT-8, but not CMT-1, was able to induce apoptosis in multidrug resistant HL60R and in Fas-ligand resistant HUT78B1 cell lines. These properties, together with others previously described (e.g. anti-metastatic and anti-osteolytic activities), suggest that CMT-8 may have important applications in the clinical management of cancer. 5 The comparative analysis of structure-activity relationship of CMT-8 and doxycycline suggests that the C-5 hydroxy moiety may play an important role in conferring activity in multidrug resistant cells. These ®ndings appear to support the hypothesis that CMT-8 may represent an interesting lead for the development of a new class of potent apoptosis inducer agents active in multidrug resistant and Fas-ligand resistant malignancies.

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Structure−Activity Relationship Studies of Novel Heteroretinoids: Induction of Apoptosis in the HL-60 Cell Line by a Novel Isoxazole-Containing Heteroretinoid

Cited by 50 publications

References 30 publications

Identification of HDAC6‐Selective Inhibitors of Low Cancer Cell Cytotoxicity

Identification of HDAC6‐Selective Inhibitors of Low Cancer Cell Cytotoxicity

A Simple and Efficient Strategy Towards Eleven‐Membered Carbocycles via Novel Synthetic Transformations of Pentafulvenes

Effects of chemically modified tetracyclines (CMTs) in sensitive, multidrug resistant and apoptosis resistant leukaemia cell lines

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