Current Medicinal Chemistry - Volume 8, Issue 12, 2001

Combinatorial technology for the generation of molecular diversity has evolved as an integrated component in accelerated drug discovery process. During the emerging days of combinatorial chemistry, solid-phase organic synthesis has been the leading strategy for the production of large libraries for lead discovery. As combinatorial techniques for the library synthesis has evolved, solution-phase synthesis of smaller, targeted libraries is gaining attention. Numerous syntheses of biologically active chemical libraries of small molecules have been reported during the past decade. This review will focus only on the recent literature of chemical libraries targeted towards anticancer properties. The synthesis, chemistry and biological activity of these libraries as anticancer agents are summarized.

The development of therapies which are selective for tumor tissues is one of the most important goals in anticancer research. Within this framework photochemotherapy can be considered a very promising approach. Its therapeutic effectiveness depends on two connected factors: drug and light. The drug (photosensitizer) is able to exert an antiproliferative effect only after interaction with suitable light. Both the photosensitizing drug and light alone are ineffective at doses used for these treatments. Nowadays, photochemotherapy is used in the treatment of cutaneous T-cell lymphoma and cavitary tumors. In the first case the photosensitizer is a psoralen derivative (P) and long-wavelength ultraviolet radiation (UVA) is used (PUVA therapy). In the second case, the treatment with porphyrins, porphyrin-based and non porphyrin-based photosensitizers is followed by irradiation with 600-1000 nm light (photodynamic therapy, PDT). This review is concerned with PUVA and PDT treatments of cancer. The molecular mechanisms considered accountable for the photochemotherapeutic effects are discussed, the development of new chemical structures aimed at improving the effectiveness and / or overcoming some undesired side effects will also be reported. Moreover, some clinical applications will be described.

Farnesyl protein transferase (FPT) inhibition is an interesting and promising approach to non-cytotoxic anticancer therapy. Research in this area has resulted in several orally active compounds that are currently in clinical evaluation. This review focuses on FPT inhibitors in clinical trials and concentrates on the benzocycloheptapyridine class, with details on the discovery and development of SCH 66336, currently in Phase II clinical trials.

The development of farnesyltransferase inhibitors (FTIs) has been one of the most active areas of anticancer drug development for the past ten years. This review presents a general overview of the developments in this area, along with a critical appraisal of the anticancer activity of FTIs. A historical survey of the protein prenylation field is given, in particular to emphasize the key role played by the Ras oncoprotein in driving the discovery of prenyltransferase enzymes. The different classes of prenylated proteins will be described along with the biochemical characteristics of the key drug target - farnesyltransferase (FTase). Numerous potent farnesyltransferase inhibitors have been developed. The FTIs developed can be separated into three different categories, based on their origin and / or mechanism of action: a) natural products b) peptidomimetics and other CAAX-competitive inhibitors c) farnesyl pyrophosphate (FPP) mimetics or analogs and other FPP-competitive inhibitors. Along with a survey of newer FTIs in each class, the development of several representative, potent compounds will be discussed in depth as we discuss the potential advantages and liabilities of each class. Particular emphasis is given to the discovery of new, more potent FPP-competitive FTIs of several diverse structural classes. Testing of different FTIs for their ability to block the growth of various cancer cell types in animal models will be discussed. There are a number of key differences between these compounds and traditional cytotoxic cancer chemotherapeutic agents, with surprising exceptions to their expected modes of action. As some FTIs have entered human clinical trials, answers may soon become available to key mechanistic questions concerning the extent and nature of their antitumor growth properties.

Natural Products have long been a fertile source of cure for cancer, which is projected to become the major causes of death in this century. However, there is a continuing need for development of new anticancer drugs, drug combinations and chemotherapy strategies, by methodical and scientific exploration of enormous pool of synthetic, biological and natural products.There are at least 250,000 species of plants out of which more than one thousand plants have been found to possess significant anticancer properties. While many molecules obtained from nature have shown wonders, there are a huge number of molecules that still either remains to be trapped or studied in details by the medicinal chemists. The article reviews many such structures and their related chemistry along with the recent advances in understanding mechanism of action and structure-function relationships of nature derived anti-cancer agents at the molecular, cellular and physiological levels. Taxol, one of the most outstanding agents, has been found beneficial in treatment of refractory ovarian, breast and other cancers. Another prominent molecule includes Podophyllotoxin. Synthetic modification of this molecule led to the development of Etoposide, known to be effective for small cell cancers of the lungs and testes. Camptothecin isolated from Camptotheca acuminata also have been extensively studied. Other important molecules discussed include Vincristine, Vinblastine, Colchicine, Ellipticine and Lepachol along with Flavopiridol, a semi-synthetic analogue of the chromone alkaloid Rohitukine from India, a pyridoindole alkaloid from leaves of Ochrosia species and many more. The review also deals with the lesser-known plants of sub-Himalayan region.

As a result of substantial advances in recent cancer biology, cell cycle regulation in the G1 phase has attracted a great deal of attention as a promising target for the research and treatment of cancer. Many of the important genes associated with G1 regulation have been shown to play a key role in proliferation, differentiation and oncogenic transformation and programmed cell death (apoptosis). Currently, a variety of cytostatic agents that affects G1 progression and / or G1 / S transition are being evaluated in clinical trials. Flavopiridol is a potent inhibitor of cyclin-dependent kinases (CDKs). UCN-01 was originally found to be a PKC-selective protein kinase antagonist. More recent studies have revealed that this agent can also inhibit several CDKs and the checkpoint kinase CHK1. FR901228, MS-27-275 and SAHA are histone deacetylase inhibitors that induce changes in the transcription of specific genes via the hyperacetylation of histones. The proteasome inhibitor PS-341 disrupts the degradation process of intracellular proteins, including cell cycle regulatory proteins such as cyclins. R115777, SCH66336 and BMS-214662 are non-peptidic farnesyl transferase inhibitors that prevent p21 ras oncogene activation. Rapamycin derivative CCI-779 downregulates signals through S6 kinase and FRAP (FKBP-rapamycin associating protein), affecting the expression levels of mRNAs important for progression from G1 to S phase. 17-Allylaminogeldanamycin targets the Hsp-90 (heat shock protein-90) family of cellular chaperones regulating the function of signaling proteins. TNP-470 (AGM-1470), a fumagillin derivative shows antiangiogenic action through binding to MetAP-2 (methionine aminopeptidase-2). The antitumor sulfonamide E7070, causing a cellular accumulation in the G1 phase, has been shown to suppress the activation of CDK2 and cyclin E expression in HCT116 colorectal cancer cell line highly sensitive to the drug. With respect to several growth factor receptors such as EGFR, PDGFR, bFGFR and VEGFR, potent and specific inhibitors of receptor tyrosine kinases have been also examined as hopeful drug candidates. In this report, we review the current status of extensive efforts directed towards the discovery and development of new chemotherapeutic anticancer agents targeting cell cycle regulation in the G1 phase, with particular focus on the compounds undergoing clinical investigations.

Inhibitors of histone deacetylase (HDAC) are an emerging class of anticancer agents. They induce hyperacetylation in chromatin usually resulting in activation of certain genes. They induce terminal cell differentiation and / or apoptosis in cancer cells. Histone deacetylase activity is recruited by co-repressor proteins to certain regions of the chromatin and aberrant histone acetylation caused by that recruitment is responsible for the pathogenesis of certain cancers on a molecular level. Inhibitors of HDAC have been identified in natural sources and also synthetic inhibitors are available. The best studied inhibitor is trichostatin A, a hydroxamic acid that exerts its activity by complexa-tion of a zinc ion that is supposed to mediate the acetamide cleavage at the catalytic site. There are several synthetic hydroxamic acids that bear resemblance to trichostatin. Another class of potent inhibitors are naturally occurring and synthetic cyclotetrapeptides that all contain an unusual amino acid with an epoxyketone, ketone or hydroxamic acid function in the side chain. Phenylacetate, phenylbutyrate, butyrate and similar short chain fatty acids are also weak inhibitors. Further inhibitors from natural sources are the epoxide depudecin and depsipeptide FR 901228. The benzamide MS-275 belongs to a new class of synthetic HDAC inhibitors and displays oral activity in animal models. First clinical studies have shown that histone hyperacetylation can be achieved safely in humans and that treatment of cancer is possible. Thus, inhibitors of HDAC are one of the most promising class of new anticancer agents. New screening assays are useful tools that will facilitate identification of further inhibitors.

Polycyclic aromatic hydrocarbons (PAH) are considered potentially carcinogenic. Substituted PAH derivatives, in contrast, may serve as anticancer agents, and as chemotherapeutics. This article presents a review of their use. Particular emphasis is placed on the synthesis of these new compounds, electrophilic substitution reactions and novel synthetic methodologies developed in our laboratory. Based on numerous reports and the data available, we believe that DNA-intercalating and membrane-interacting sites are the target for their effects.