Anti-HIV alkaloids

Recently, the anti-HIV alkaloids michellamines A (4) and B (5) have attracted much attention. The tetraaryl skeleton of the michellamines is constructed by first forming the inner (nonstereogenic) biaryl axis and then adding the two other (stereogenic) axes by means of a double Suzulci-type cross-coupling reaction between binaphthalene ditriflate (2) and iso-quinolineboronic acid (3) (Eq. (13)) [31]. 

Most recently, the anti-HIV alkaloids michellamines A and B have snccessfully been synthesized by a double Suzuki-type cross-coupling reaction between a binaphthalene ditriflate and an isoquinoUneboronic acid (Scheme... 

Okamoto M, Ono M, Baba M. Potent inhibition of HIV type 1 replication by an anti-inflammatory alkaloid, cepharanthine, in chronically infected monocytic cells. Res Hum Retroviruses 1998 14 1239-1245. 

Castanospermine is a plant alkaloid isolated from the seeds of the Australian chestnut tree, Castanospermium australe. As with most anti-HIV inhibitors, the discovery of the compound predates the time of isolation of HIV-1. The compound inhibits a-glucosidase-1, and therefore normal processing of the glycopro-... 

Buxus alkaloids have a imique steroid-triterpenoid pregnane type skeleton with C-4 methyls, 9fl, lOp cycloartenol system with a degraded C-20 side chain [21-33]. These alkaloids exhibit varions biological activities including anti-HIV, anti-TB,... 

In 1990, Lange et al. isolated O-methylmukonal (38) from the roots of Murray a siamensis (57). Two years later, Bhattacharyya et al. reported the isolation of the same alkaloid from the roots of a different natural source, G. pentaphylla, and named it glycosinine (38) (24). More recently, Kongkathip et al. reported the isolation of O-methylmukonal (38) from the rhizomes and the roots of another natural source, C. excavata (58). Moreover, they reported for the first time that 38 showed anti-HIV-1 activity. 

In 1996, Wu et al. isolated clausine H (50) and clausine K (51) from the stem bark of C. excavata (46). These alkaloids showed an inhibition of rabbit platelet aggregation and caused vasocontraction. Later, Ito et al. isolated clausine H and clausine K from the same natural source and named them clauszoline C (50) (74) and clauszoline-J (51) (47). More recently, Kongkathip et al. isolated clauszoline-J (51) from the rhizomes and roots of the same natural source, C. excavata, and described its anti-HIV-1 activity (58). 

In 2000, Boyd et al. reported for the first time an anti-HIV active carbazole alkaloid, siamenol (89) (see Scheme 2.17). This prenylated carbazole alkaloid inhibited HIV-1 induced cytopathic inhibitor activity in an XTT-tetrazolium assay with EC50 2.6 pg/mL (85,449). Recently, Kongkathip et al. reported anti-HIV-1 activity for O-methylmukonal (glycosinine) (38) (see Scheme 2.9), 7-methoxy-O-methylmu-konal (2,7-dimethoxy-3-formylcarbazole) (48) (see Scheme 2.10), and clausine K (clausazoline-J) (51). These studies showed strong anti-HIV-1 activity for... 

The total synthesis of litseaverticillols D, F and G (172 and 173), which are natural products with anti-HIV activity, was achieved recently via a singlet oxygen initiated cascade proposed to be biomimetic (Scheme 64). Finally, allylic alcohols 174a and 174b (Scheme 64) were isolated in a 4/1 ratio via a stereoselective singlet oxygen ene reaction. Stereoisomer 174a is an intermediate in the synthetic route of staurosporine, which is a bioactive alkaloid with hypotensive, antimicrobial and cell cytotoxic properties. 

In another processing procedure, Platis and Fabrou (2006) purihed anti-HIV MAb from plants using a PEG/Pi aqueous two-phase system. This techihque purihes the plant extract from any additional alkaloids and phe-nolics. The sample can then be applied to a protein A or G affinity column without the need for any further treatment. The authors were able to use this techihque to achieve over 95% recovery. 

As representative of the derivatives of pyridoacridine, eilatin, a marine alkaloid inhibits in vitro cell proliferation in chronic myeloid leukemia patients [244], Other members of the pyridoacridines, such as alkaloids isolated from a Cystodytes sp. ascidian, inhibit topoisomerase II [245], Additionally, analogues derivatives of these type of alkaloids showed interesting anti-HIV activity [246],... 

Avarol and avarone derivatives (from the Red Sea sponge Dysidea cinerea), the alkaloids psy-chotrine and O-methylpsychotrine (from ipecac, the dried rhizome and root of Cephaelis ipecacuanha), and phloroglucinol derivatives such as mallotojaponin, from the pericarps of Mallotus japonicus, have all been reported to inhibit the reverse transcriptase activity of HIV-1, noncom-petitively with respect to the natural substrate (dNTP). In neither case was the anti-HIV-1 activity determined in cell culture, so it is not clear whether any of these compounds is really an effective... 

Microbial formation of plant isoquinolines became an attractive issue over recent years [116]. Magnoflorine was of particular interest thanks to its pharmacological activities. On one hand, it was found that this aporphine alkaloid protects human high density lipoprotein (HDL) against lipid peroxidation but it also exhibits anti-HIV activity [117-119]. New production strategies for this alkaloid will be vital in the future. 

With nearly 20 years of experience on plant-derived natural products, NPRL has identified numerous active anti-HIV compounds including polycyclic diones, saponins, alkaloids, triterpenes, polyphenols, flavonoids and coumarins. Triterpenes have diverse structures and pharmacological activities. 

Acetate is also a precursor of several groups of alkaloids in the form of a polyketide chain that interacts with an unknown nitrogen source (as in the terpene alkaloids). Examples of acetate-derived alkaloids are coniine—the toxic principle of Conium maculatum, pinidine—from several Pinus species, and the naphthy-lisoquinoline alkaloids (e.g., ancistrocladine)—showing antimalarial and anti-HIV activity. The latter alkaloids are apparently derived from the oxidative coupling of two pentaketide units. Huperzine A, currently in clinical trials for the treatment of Alzheimer s disease and isolated from the club moss (Serrata huperzia), is derived from a polyacetate precursor (Fig. 46). 

Anti-HIV compounds from marine sources also included terpenoids, steroids, peptides and alkaloids. Avarol, Fig. (1) and avarone. Fig. (2), sesquiterpenoid hydroquinones from the marine sponge Dysidea cinerea, are promising anti-HIV compounds [41,42]. Three new... 

Quite recently, the use of natural cinchona alkaloids as catalysts for the intramolecular oxo-Michael addition of o-tigloylphenol (3), furnishing chiral ris-2,3-dimethyl-4-chromanone 4, which is a valuable intermediate for the synthesis of the anti-HIV-1 active coumarins, (+ )-calanolide A (5a), and (+ )-inophyllum B (5b), was reexamined by Ishikawa and coworkers (Scheme 9.2) [2], The parent cinchona alkaloids,... 

Tseng and colleagues [58] reported a three-step synthesis of fused tetrahydro-P-carbolinequinoxalinones, solely based on the use of ionic liquids as solvents. Tetrahydro-P-carboline is a central core for many biologically important indole alkaloids, and the moiety of quinoxalinone often exhibits a wide spectrum of biological activities such as being anti-HIV, antihypertensive, and a ligand for a number of protein receptors. As a first step, tryptophan methyl ester was reacted with an aldehyde to form tetrahydro-p-carboline by Pictet-Spengler cyclization that further reacted with l-fluoro-2-nitrobenzene to form iV-aryl-tetrahydro-P-carboline. Intramolecular cyclization upon a reduction reaction in step three provided the desired tetrahydro-P-carbolinequinoxalinones. The entire process was based on the use of 1-n-butyl-... 

Much of the current interest in making simple derivatives of (+ )-castanospermine (239) can be traced to a seminal publication in 1989, which showed that the alkaloid s anti-HIV activity could be increased by as much as twenty times upon esterification (216). Positionally selective acylation procedures usually involve sequential protection, acylation, and deprotection steps e.g. the preparation of esters at the C-6 and C-7 (217) or the C-8 hydroxy groups (218). Also of interest are procedures that take advantage of enzyme-catalyzed transesterification with activated esters, e.g. the use of subtilisin for ester formation at C-1, pancreatic porcine lipase for preferential reaction at C-6 and C-7 (219-221), and cross-linked enzyme crystals (CLECs) of subtilisin for making the potentially valuable antitumor agent 1-0-butanoylcastanospermine (222). A cautionary note was sounded, however, when it was observed that 6-0-acyl castanospermine esters could equilibrate to a mixture of... 

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