Mini Reviews in Medicinal Chemistry - Volume 11, Issue 3, 2011

The serine/threonine protein kinase C (PKC) family was first identified as intracellular receptor(s) for the tumor promoting agents phorbol esters. Thirty years after the discovery of PKC, the role of specific PKC isoforms has been described in relationship with an altered pattern of expression in different types of cancer and a good number of small molecule inhibitors (inhibitory peptides, antisense oligonucleotides or natural compounds) targeting PKC are now available. Despite all these achievements and a huge amount of basic research studies on the biochemical regulation of PKC, there has been a delay in clinical trials with drugs targeting PKC function. This delay is easily explained taking into account the extreme biological complexity of the PKC family of isoforms and the incomplete understanding of the specific role of each PKC isozyme in different types of cancers. Some of the difficulties in developing pharmacological compounds selectively tuning the different PKCs have started to be overcome. In this review, the growing evidences of the role of the PKC isoforms α, βII, δ, ε, ζ and ι is in promoting or counteracting tumor progression will be discussed in relationship with promising therapeutic perspectives.

The Hedgehog signalling pathway plays a critical role in controlling growth, especially during development, but is often over-activated in tumourigenesis. It has recently emerged as an important target for anticancer drugs, with several compounds in clinical trials. This review initially describes the Hedgehog pathway, focussing on the Patched receptor, and the Smoothened GPCR-like protein, as well as discussing the role of Cancer Stem Cells. It subsequently presents the discovery and development of drugs targeting this pathway. The initial focus is on cyclopamine - the first compound discovered that could inhibit the Hedgehog pathway - and selected cyclopamine analogues, including a review of the development of IPI-926. In addition, a number of other compounds are briefly discussed, to give an overview of current therapies in clinical development, and to indicate the possibilities for targeting different parts of the Hedgehog pathway in future. Finally, combination chemotherapy - incorporating a Hedgehog pathway inhibitor as well as another drug - is discussed from the perspective of drug resistance and effects on cancer stem cells.

Cisplatin and its congeners are well-known to exert their therapeutic effects on cancer via interaction with DNA in the cell nucleus. On the other hand, the undesirable side-effects of these drugs appear to also be linked, at least to some extent, to interaction of the platinum with proteins and peptides. For other classes of anticancer drugs, interaction with proteins is in fact the primary pathway whereby therapeutically-useful effects are achieved. Here, a review is given of the known instances of interaction of cisplatin and related compounds with proteins and biologically relevant peptides, with emphasis on structural and reactivity aspects.

Natural Guanidines from marine invertebrates represent a group of bioactive secondary metabolites that revealed prominent pharmacological activities such as antimicrobial, antiproliferative, analgesic, and anticoagulant properties. Acyclovir (Zovirax®), the first guanidine-derived pharmaceutical for the treatment of herpes infections since late 1970s, was synthesized based on a marine arabinosyl nucleoside, spongosine. Recently, ziconotide (Prialt®), a synthetic form of the marine-derived peptide (ω-conotoxin MVIIA) comprising a guanidine moiety, has been approved for the treatment of chronic pain. This review surveys over 130 compounds of guanidine-containing secondary metabolites from marine invertebrates with emphasis on their pharmacological significance and structure-activity relationships.

Acetylcholinesterase (AChE) inhibitors are considered as promising therapeutic agents for the treatment of several neurological disorders such as Alzheimer's disease (AD), senile dementia, ataxia and myasthenia gravis. There are only few synthetic medicines with adverse effects, available for treatment of cognitive dysfunction and memory loss associated with these diseases. A variety of plants has been reported to possess AChE inhibitory activity and so may be relevant to the treatment of neurodegenerative disorders such as AD. Hence, developing potential AChE inhibitors from botanicals is the need of the day. This review will cover some of the promising acetylcholinesterase inhibitors isolated from plants with proven in vitro and in vivo activities with concern to their structure activity relationship.

Myocardial tissue engineering involves the design of biomaterial scaffolds, aiming at regenerating necrotic myocardium after myocardial infarction. Biomaterials provide mechanical support to the infarct area and they can be used as vehicles for sustained and controlled local administration of cells and growth factors. Although promising results have been reported in experimental studies, many issues need to be addressed before human use.