Combretastatin analogue

Ombrabulin (AVE8062, AC-7700) 58 (Sanofi-Aventis) is being evaluated in Phase II/III trials as a treatment for advanced stage soft tissue sarcoma for patients who have failed previous anthracycline and ifosfamide treatments.124 Ombrabulin 58125 128 is a synthetic combretastatin analogue that was licensed by Sanofi-Aventis from Ajinomoto and is also a vascular disrupting agent. 

The potency of the 3 -amino-4 -dimethylamino analogue against a panel of tumor cell lines (P-388, A-549, HT-29, MEL-28 or HeLa, HI 16, H-60) is even higher than that of Combretastatin A-4 or the related 3 -amino analogue. It is remarkable that this derivative, which is the most cytotoxic, has no effect on tubulin polymerization at concentrations below 30 )iM. This fact is in contrast to the usual behaviour of other combretastatin analogues, which always display a strong inhibitory effect on tubulin polymerization whenever they are cytotoxic in the submicromolar range. 

The synthesis of many combretastatin analogues (e.g., 18a, 18b, and 18c) clearly illustrates the power of a relatively simple natural product structure to spawn a prolific output of medicinal and combinatorial chem-... 

Phase I, pharmacokinetic, and DCE-MRI correlative study of AVE8062A, an antivascular combretastatin analogue, administered weekly for 3 weeks every 28 days, was reported [43]. Nine patients received 48 infusions of AVE8062. Cardiovascular effects consisting of asymptomatic systolic hypotension without elevation of CPK or troponin I levels or ECG changes were observed. Decreased tumor blood flow was observed by DCE-MRI at the 15.5 mg/m dose level. The half-life of AVE8062 was 15 min, but an active metabolite was formed with a half-life of 7 h. 

Concerning combretastatins, the biophores involving dihydrocombretastatins and combretastatin A-2 analogues mainly indicated the importance of the two carbon bridge, whereas the single CA4 biophore was unable to efficiently describe the activity of CA4 analogues. 

CoMFA CA4 analogues Hypothesis of a different pharmacophore for combretastatins and the other CSI colchicine, podophyllotoxin and phenstatin [26]... 

The relative molecular simplicity of combretastatins and resveratrol, associated with their important anticancer properties, offers promises for the rational design of new chemotherapeutic agents. The interest in these compounds is evident from the great number of papers published every years, covering various aspects, chemical and biological. For this reason in this paper the attention will be focused on Combretastatins. The majority of compounds reported in the paper are in fact considered their derivatives or analogues, albeit some of them, e.g. 3,4,5-trimethoxy-4 -substituted stilbenes have been considered resveratrol analogues. 

Other derivatives were synthesized where the 3 substituent was in turn an halide [14], a nitrogen quaternary salt-containing side chains [15], an O-alkylamine [15], a nitro group [15], an azido group [16], a functionalized C-2 unit [17]. Several fluorinated analogues of Combretastatins A-1 and A-4 were synthesized and their in vitro anticancer properties determined. The most active fluoro analogue 3 -deoxy-3 -fluoro-combretastatin A-4 retains the potent cell growth inhibitory properties of Combretastatin A-4 [14]. 

Recently a boronic acid residue was used to mimic the 3 -OH in Combretastatin A-4 the biological data demonstrated that the cis boronic acid analogue is a viable bioisostere of Combretastatin A-4 [18]. 

A wide range of structural analogues have been reported, which include substitution of the A- and/or B-ring in the combretastatin framework with different carbo- and heteroeycles. Some examples are reported below. 

Even though the introduction of a naphthalene system keeps most of the potency of combretastatins, their low aqueous solubility is a main drawback in order to assay these compounds in vivo. To overcome this problem a new family of analogues replacing the naphthalene moiety by a quinoline or quinoxaline system was synthesized. Fig. (8) [25]. 

Isoxazoline or isoxazole analogues represent an other series of Combretastatin A-4 analogues where the alkenyl motif of Combretastatin A-4 was replaced by a five-membered heterocycle (isoxazoline or isoxazole). The synthetic strategy to isoxazolines or isoxazoles bearing two aromatic rings on position 4,5 is reported in the Scheme 9 [30]. 

The Combretastatin A-4 analogues, containing a variety of heterocyclic moieties, such as imidazoles, thiazoles and tetrazoles, not only display efficient inhibition of tubulin polymerization but also exert potent cellular growth inhibition in different cancer lines including MDR cancer cells. It is worthy to note that some of Combretastatin A-4 analogues, such as imidazole-based Combretastatin A-4 exhibited oral availability leading to solid tumor regression in vivo tumor models. 

Diols and derivatives. In the Combretastatins A family, the corresponding (E) stilbenes and bibenzyls, e.g. Combretastatin B-1 and analogues, which contain an -hybridized freely rotating ethane bridge, exhibit a decrease in antineoplastic activity when compared to the corresponding (Z)-stilbenes. To explore the possible conversion of the inactive ( )-isomer of Combretastatins A-1 and A-4 into a more active derivatives, a series of compounds was synthesized where the (E)-olefin unit was replaced by a freely rotating 5/73-hybridized chiral C-2 unit [35, 36]. 

The combretastatin A-4 diaryl aniline analogue 67 was prepared in a similar manner via Pd(II)-catalyzed coupling of 3,4,5-trimethoxy bromobenzene and a benzyl-protected aniline using another of the Buchwald protocols (Scheme 18). 

For this reason, in the present section few lead, most active, compounds have been chosen for each class of derivatives or analogues, as divided in the previous sections their activities have been reported in comparison with that of a reference compound (usually Combretastatin A-4) to minimize the problems inherent to different experimental protocols for their determination. Fig. (19-21). 

Investigation of a large variety of synthetic analogues evidenced that the hydroxyl group at the C-3 position of Combretastatin A-4 can be substituted with a different group or atom. 

It must be noted that the 7-quinolyl derivative has a nitrogen atom at the same relative position as the highly potent 3 -amine analogue of Combretastatin A-4. 

The pyrazole- and thiazole analogues of the 3 -deoxy-3 -amino-4 -methoxy Combretastatin A-4 showed potent antimitotic (IC50 3.0 pM and IC50 10 pM) activity. The former showed also a potent cytotoxic activity (IC50 8.4 nM ). Moderate antimitotic activity (IC50 3.0 pM) and weak cytotoxic activity was observed for a triazole derivative, whereas tetrazole ring confers potent antimitotic (ICso 2.0 pM) as well as cytotoxic activity. Compounds with potent cjdotoxicity were further evaluated in vivo in the Colon murine tumor model. The best antitumor activity in vivo, expressed as tumour growth suppression, was observed for the thiazole and tetrazole derivatives with values comparable to the ones observed for 3 -deoxy-3 -amino Combretastatin A-4 hydrochloride. 

In summary, the Combretastatin A-4 analogues, containing a variety of heterocyclic moieties, such as pyrazoles, imidazoles, thiazoles and tetrazoles, not only display efficient inhibition of tubulin polymerization... 

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