Synthesis of conjugates based on chlorin and isosteviol building blocks

Abstract

Conjugates containing ent-beyerane carbocyclic frameworks on the periphery of a porphyrin macrocycle were prepared by acylation of chlorin e 6 derivatives with hydroxyl and amino groups using ent-16-ketobeyeran-19-oic acid chloride (diterpenoid isosteviol).Chlorophyll a derivatives such as chlorin e 6 amides and pyropheophorbide a in addition to many others are currently being investigated as photosensitizers for photodynamic therapy of oncological and viral diseases. Several of them are the active ingredients in preparations that are already used in clinical practice [1]. We have used the diterpenoid isosteviol (ent-16-ketobeyeran-19-oic acid, 1), which exhibits various types of physiological activity (hypotensive and antihypertensive effects [2], inhibition of oxidative phosphorylation [3], reduction of ATP-activity of certain phosphotases and oxidases [4]), to modify amino-and hydroxychlorins. The biological activity of isosteviol and its derivatives is due mainly to their interaction with cell membranes [2][3][4]. Model experiments showed that certain isosteviol derivatives can facilitate the transport of amino acids through membranes [5,6]. Thus, it can be surmised that introducing onto the periphery of the chlorin macrocycle an isosteviol moiety, which is a functionalized ent-beyerane carbocyclic diterpenoid framework, will facilitate better interaction of the synthesized conjugate with cell membranes. This will increase the photosensitizing effect and could result in the preparation of new biologically active compounds.We used an acylation reaction to introduce the ent-beyerane carbocyclic framework onto the periphery of the chlorin ring. The acylating agent was isosteviol acid chloride (2), which was prepared using thioyl chloride and isosteviol (1) [7] (Scheme 1). Amino and hydroxy groups that were convenient for acylation were introduced onto the periphery of the chlorin macrocycle using opening of the exocycle of methylpheophorbide a (3) [8-11] to synthesize amino-and hydroxychlorins (4-6). Opening of the exocycle by ethylenediamine in combination with amidation of the ester substituent in the 17-position by the same diamine produced a chlorin (10) with two amino groups [12].Hydroxy and amino groups of the chlorins (4-6 and 10) were acylated by isosteviol acid chloride (2) by refluxing in THF in the presence of an excess of triethylamine (Scheme 1). PMR spectra of all three compounds (6-8) showed resonances at strong field for protons of the isosteviol moiety, in particular 3H singlets for methyls. Furthermore, PMR spectra of 7 and 8 exhibited an additional broad triplet for the amide that was formed by acylation of the amine by 2. Using diaminochlorin 10 as the substrate for the acylation and a two-fold molar excess of 2 produced in 30% yield a chlorin with two diterpenoid moieties (11) (Scheme 1). PMR spectra of 11 had two additional broad triplets of amides that were formed by acylation of diaminochlorin with 2 when compared with the spectrum of starting 10. Furthermore, a doubled set of singlets fo...

Bioactivity Profile of the Diterpene Isosteviol and its Derivatives

“…Density functional theory calculations showed that the hydroxyl group on one side and the carboxyl group oxygen on the other side are the centers of the electron density localization and the hydrogen atoms are the most electropositive in its structure [ 35 ]. Calixarenes is one of the best examples of such carriers compounds that is enormously used in medicinal chemistry [ 34 , 36 , 37 , 38 , 39 , 40 ]. The synthesis of isosteviol based cages as a drug carrier needs to be explored as they are suitable carrier molecules.…”