Dual inhibitors of inosine monophosphate dehydrogenase and histone deacetylase based on a cinnamic hydroxamic acid core structure

doi:10.1016/j.bmc.2010.06.081

Bioorganic & Medicinal Chemistry

Volume 18, Issue 16, 15 August 2010, Pages 5950-5964

https://doi.org/10.1016/j.bmc.2010.06.081 Get rights and content

Abstract

Small molecules that act on multiple biological targets have been proposed to combat the drug resistance commonly observed for cancer chemotherapy. By combining the structural features of known inhibitors of inosine monophosphate dehydrogense (IMPDH) and histone deacetylase (HDAC), dual inhibitors of IMPDH and HDAC based on the scaffold of cinnamic hydroxamic acid (CHA) have been designed, synthesized, and evaluated in biological assays. Key features, including the linker length, linker functionality, substitution position, and interacting groups, have been explored. Their individual contribution to the inhibitory activities against human IMPDH1 and IMPDH2 as well as HDAC has been assessed.

Graphical abstract

Introduction

Cancer cells have been characterized as those that can sustain their growth, escape growth inhibition and evade apoptosis.¹ This lack of control has been attributed to genetic mutations and functional alterations of proteins that are involved in signal transductions and cellular regulations. Extensive biological research has delineated diverse signaling pathways that regulate the processes of cell proliferation, differentiation, and apoptosis. Such information has inspired and facilitated the design of a wide range of small molecules and macromolecular biologics that target the precise mechanisms causing and driving the pathological process of a particular type of cancer. A number of targeted anticancer therapeutics have entered clinical trials and many have been approved for clinical use, greatly improving the treatment of various cancers. However, resistance to targeted therapeutics usually occurs due to gene amplification, amino acid point mutation, function redundancy and pathway cross-talking, severely reducing the efficacy of targeted therapy.²

The success of and challenges faced by targeted anticancer therapeutics can be exemplified by imatinib mesylate, currently a first line therapy for chronic myelogenous leukemia (CML). The hallmark of CML is Philadelphia (Ph) chromosome derived from a chromosomal translocation that fuses the genes of Bcr and Abl. The resultant Bcr-Abl tyrosine kinase is constitutively active and is expressed in 95% of CML, representing an extremely attractive target for CML therapy.³ Imatinib inhibits this aberrant Bcr-Abl chimeric protein and interrupts the subsequent signaling cascades that eventually lead to deregulated proliferation. Imatinib has revolutionized the treatment of CML and established itself as a model for future discovery and development of targeted anticancer therapeutics. However, resistance to imatinib frequently stems from amplification of Bcr-Abl gene. More significantly, a growing number of point mutations have emerged, either interrupting imatinib’s binding in the ATP binding pocket or preventing Bcr-Abl from adopting the inactive conformation to which imatinib binds.⁴ The second generation of Bcr-Abl inhibitors such as nilotinib and dasatinib are able to overcome a majority of Bcr-Abl mutations. However, T315I, a critical mutation, still remains elusive.⁴

Consequently, there is an urgent need for new approaches to combat the inevitable drug resistance.⁵ One strategy is to combine a targeted therapy with conventional anticancer agents or another targeted therapy. Another strategy is to design and develop a drug that simultaneously inhibits a broad spectrum of biological targets. For instance, multi-kinase inhibitors have been actively pursued for the treatment of cancers.⁶ However, a broad spectrum inhibitor usually acts on protein targets in the same family or in closely related families. As a result, cross resistance is a potential drawback.

We report herein our design, synthesis and biological evaluation of a new class of anticancer agents that inhibit both inosine monophosphate dehydrogenase (IMPDH) and histone deacetylase (HDAC). Blockage of both IMPDH and HDAC, two well-established anticancer targets with significantly different mechanisms, could reduce the probability of drug induced resistance and cross resistance.

HDAC catalyzes the deactylation of the acetyl lysine residue on histone tails. There are 18 members of human HDAC which are categorized into four classes. Class I, II, and IV HDACs require zinc metal while Class III HDACs (SIRTs) are NAD-dependent. Together with histone acetyltransferase (HAT), HDAC controls the histone acetylation level and subsequent gene expression through chromatin modification. It has been suggested that HDAC inhibitors allow the expression of certain genes that are suppressed in cancer cells.⁷ In addition, a wide range of non-histone proteins have been discovered as HDAC substrates, many of which have been suggested to be important targets for cancer therapy.8, 9 Suberoylanilide hydroxamic acid (SAHA, vorinostat) (1, Fig. 1) and romidepsin (7, Fig. 1) have been approved by the Food and Drug Administration (FDA), validating HDAC inhibitors as anticancer therapeutics.

IMPDH, a nicotinamide adenine dinucleotide (NAD)-dependent enzyme,¹⁰ catalyzes a rate-limiting step in the de novo synthesis of guanine nucleotides, which are crucial for cell growth and proliferation. There are two forms of human IMPDH, type 1 and type 2. The type 2 isoform (hIMPDH2) is selectively up-regulated in proliferating cells while the type 1 isoform (hIMPDH1) has been shown to play a key role in angiogenesis, establishing IMPDH as an attractive target for anticancer drug discovery.11, 12

Section snippets

Design

Our design of dual inhibitors was based on a premise that inhibitors targeting one enzyme can be structurally modified without compromising their initial activity while simultaneously enhancing their activity against a second target. We anticipated that key features present in individual IMPDH and HDAC inhibitors could be combined or merged into one single molecule without compromising the activity against either target. Our design was prompted by an examination of known HDAC and IMPDH

Conclusions

By combining structural features from known inhibitors of IMPDH and HDAC, we have been able to design, synthesize and evaluate a new type of dual inhibitors of IMPDH and HDAC based on a CHA core structure. Two series of compounds, namely the aminomethyl CHA and amino CHA series, have been conceived. Variations of key components in either series allowed us to assess the individual contribution of these elements. In the aminomethyl CHA series, a meta-substitution pattern is desired for improved

General methods

All commercial reagents (Sigma–Aldrich, Acros) were used as provided unless otherwise indicated. An anhydrous solvent dispensing system (J. C. Meyer) using two packed columns of neutral alumina was used for drying THF, Et₂O, and CH₂Cl₂, while two packed columns of molecular sieves were used to dry DMF. Solvents were dispensed under argon. Flash chromatography was performed with Ultra Pure silica gel (Silicycle) with the indicated solvent system. Melting points were determined on a Mel-Temp

Acknowledgments

This research was supported by the Center for Drug Design in the Academic Health Center of the University of Minnesota. We thank Dr. Courtney Aldrich for his help with the biological assays. We also thank Dr. Yanli Xu for her help with HRMS characterization of several compounds. The University of Minnesota Supercomputing Institute provided all the computational resources.

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Dual inhibitors of inosine monophosphate dehydrogenase and histone deacetylase based on a cinnamic hydroxamic acid core structure

Abstract

Graphical abstract

Introduction

Section snippets

Design

Conclusions

General methods

Acknowledgments

Cell

Blood

Crit. Rev. Oncol. Hematol.

Cancer Cell

Immunopharmacology

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

J. Pharm. Sci.

J. Biol. Chem.

Biochim. Biophys. Acta

Nat. Rev. Drug Disc.

Haematologica

Leukemia