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2000

Current Bioactive Compounds - Volume 2, Issue 3, 2006

Volume 2, Issue 3

Volume 2, Issue 3, 2006

    • Catalysis and Inhibition of HIV-1 Protease

      https://doi.org/10.2174/1573407210602030243

      Since AIDS was first recognized in the early eighties, more than 25 million people have died and tens of millions of people have been infected with HIV. Presently more than 40 million men, women and children are living with HIV. In the most affected countries, AIDS dramatically diminishes life expectancy and economic potential, by killing people in the prime of their lives, and undermines the future generations by creating millions of orphans. Although HIV infection rates are especially dramatic in Africa and South-eastern Asia, in the most populous countries including China, Indonesia and Russia, the disease is spreading rapidly. Several targets have been identified in the search for a treatment against HIV infection, but until now only three have been successfully spotted. They correspond to two fundamental enzymes for the virus life cycle (protease (PR) and reverse transcriptase (RT)) and very recently to the event of membrane fusion between the virus and the cell. FDA has approved a total of twenty five antiretrovirals, nine of which targeting PR, fifteen RT and one targeting virus entry. Additionally, albeit in the early stages of clinical trials, there are also inhibitors being developed against the viral enzyme integrase (IN). This work deals with the inhibition of PR. This enzyme has been considered as a paradigm of success in structure based drug design, and there are more three-dimensional structures resolved for PR than for any other enzyme. The catalytic mechanism is briefly outlined. Subsequently, the rational development of PR inhibitors is discussed, the existing data for the currently in vitro and in vivo efficient compounds are compiled, and the methodologies to improve their potency and bioavailability are explained.

    • Chemistry and Biology of Novel Microtubule-Destabilizing Agents that Bind α-Tubulin

      https://doi.org/10.2174/1573407210602030269

      Bioactive compounds capable of interacting with tubulins and microtubules represent powerful weapons in cancer chemotherapy. Most of these compounds, including the well-established chemotherapeutic agents colchicine (1), podophyllotoxin (3), vinblastine (4) and vincristine (5) that interfere with the formation and growth of microtubules, or Taxol (11) and the epothilones (12-13), which promote tubulin polymerization and stabilize microtubules, share an interaction with β-tubulin, one of the two subunits of the globular heterodimeric protein tubulin. In contrast, few compounds have been identified as interacting with α-tubulin. A select group of natural compounds are pironetin (18) and the hemiasterlins, and the synthetic compounds cyanoacrylates (21-22), dinitroanilines (23-25) and tetrahydrofuranyl derivatives COBRA-0 (133) and COBRA-1 (26). In addition to their interaction with the α-tubulin subunit, all these compounds share the capacity of destabilizing microtubules. In the present review, we will discuss the most relevant aspects of the biology and chemistry of these compounds, with an emphasis on their antiproliferative properties and potential as anticancer drugs.

    • Search for and Development of Active Vitamin D3 Analogs

      https://doi.org/10.2174/1573407210602030301

      Twenty-five years ago, alfacalcidol arrived on the scene as a prodrug of the active form of vitamin D3, calcitriol [1,25(OH)2D3] to remedy vitamin D3 deficiency. With the concurrent reported discovery of the differentiation-inducing effect of active vitamin D3, its diverse physiological effects have become appreciated and the research aiming to accentuate selected physiological effects by analog synthesis has made a fresh development. Our studies aimed particularly at separating the differentiation-inducing effect/cell growth-inhibitory effect and the calcemic effect of active vitamin D3 led to the development of two characteristic analogs, OCT and ED-71. OCT, characterized by its profound differentiation-inducing effect and modest calcemic effect, is currently in practical use as an injectable therapeutic agent for secondary hyperparathyroidism as well as in clinical settings as an ointment for the treatment of psoriasis vulgaris, an intractable skin disease. The other analog, ED-71, possesses a profile inverse to that of OCT and is now under phase III clinical development as an oral preparation for treatment of osteoporosis. OCT and ED-71 are considered second generation analogs developed from first generation analogs, 1,25(OH)2D3 and alfacalcidol used in vitamin D3 formulations. In further investigation of analogs having grater activity and biological differentiation than second generation analogs, we adopted in vivo bone effects as a target effect v. in vivo calcemic effects as a side effect using ovariectomized rats. From these studies, we are currently developing third generation analogs of 1,25(OH)2D3, such as DD-281, which is also discussed in the review.

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