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RNAse mimics are small molecules that can cleave RNA in a fashion similar to ribonucleases. These compounds would be very useful as gene specific reagents if their activities could be regulated and targeted. We demonstrate here that polyamides with methionine substituents show enhanced RNA cleavage activity relative to other polyamides. Conjugation of these compounds to aminoglycosides produced RNAse mimics that are capable of inhibiting eukaryotic protein synthesis. As a new class of compounds capable of interacting with nucleic acids, these novel aminoglycoside-polyamides constitute promising scaffolds for the construction of nuclease mimics with biological activity.

Certain thiazole-containing water-soluble glycosylated polyamides were synthesized and preliminary anti-cancer evaluation carried out by NCI against three types of cancer-cells. Glycosyl moieties were introduced onto the polyamide backbone in order to increase the water-solubility of the longer polymers. This necessitated the development of novel synthetic methods. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

The biological activity of enediyne chemotherapeutic (anti-cancer) agents is attributed to their ability to cleave duplex DNA. Part of the reaction of cleavage is the abstraction of hydrogens from the deoxyribose moiety of DNA by the biradical formed via a Bergman rearrangement. The mechanism of the reaction of abstraction of two hydrogen atoms from two deoxyribophosphate molecules by the calicheamicinone biradical is studied with ab initio calculations at Hartree-Fock and post-Hartree-Fock level. The Titan program is used to perform the calculations. It is found that the reactions are exothermic and thus thermodynamically reasonable. The mechanism of DNA cleavage by the enediyne-containing drugs is likely to proceed by the abstraction of the hydrogens from deoxyribose by the biradical formed by the drug. Further studies should determine in which way the modification of the drug’s structure would make this reaction even more exothermic and, thus, more likely to occur.

The design and synthesis of the lipophilic (9) and fluorescent (10) conjugates of a structural analogue of distamycin and their in vitro cellular localization studies are reported. Confocal laser scanning microscopy (CLSM) indicates that 10 rapidly enters human ovarian adenocarcinoma (SKOV-3) cells with principal uptake in mitochondria and uniform cytoplasmic distribution.

Imidazole and compounds containing imidazole residues have been shown to cleave RNA in an RNase A-mimicking manner. Di-imidazole lexitropsin is a compound which is derived from the polyamide drugs distamycin and netropsin essentially by the replacement of two pyrrole heterocycles with N-methyl-imidazole residues. This enables it to bind to the minor groove of B-DNA in a sequence-specific manner. We demonstrate here that this lexitropsin derivative has RNA cleavage activity, as tested on model RNAs. Optimal cleavage conditions and cleavage specificity resemble those known from other imidazole conjugates and are thus consistent with an RNase A type cleavage mechanism. The optimum concentration of the compound for cleavage is similar to previously investigated imidazole-based RNase mimics. As a whole new class of chemical compounds capable of interacting with nucleic acids through extensive hydrogen bonding, these imidazole containing compounds constitute promising scaffolds and ligands, for the construction of novel RNase mimics with high affinity.

The binding of ligands to nucleic acids is of great interest for the control of gene expression and other nucleic acid mediated processes. We have evaluated the binding of several geometrically-constrained bis-distamycins to a model Okazaki fragment [OKA], or a DNA duplex having identical base sequence [DD], using gel-shift assays, optical spectroscopy and differential scanning calorimetry. In the case of covalent attachment of two distamycins to a central benzene ring, a similar binding profile was observed for [DD] as was observed for [OKA] (para binds [K(app) > 10(6) M(-1)], meta binds only weakly). For a central pyridyl ring, however, clear distinction between the binding to [DD] and binding to [OKA] was observed. While none of the three meta isomers having a central pyridyl ring bound [OKA], two of them (MT-17 and MT-12) bound [DD] [K(app) > 10(6) M(-1)]. These results demonstrate subtle differences in lexitropsin shape and placement of electronegative atoms may result in selective binding to a nucleic acid duplex based both on base sequence and chemical composition. Selective binding to DNA duplexes may be useful for designing ligands that regulate transcription, but do not interfere in other nucleic acid mediated processes.

Three types of 1-chloromethyl-5-hydroxy-1,2-dihydro-3H-benz[e]indole (seco-CBI) dimers were designed, synthesized and evaluated in vitro by NCI against nine types of cancer cells. Biological results showed that the antitumor activities of these seco-CBI dimers were strongly related to the position and length of the linker and generally with potency increasing in the order of C7-C7 dimers (22i-iv) < C7-N3 dimers (28i-iv) < N3-N3 dimers (25i-iv). Compound 28iv showed significant activity against CCRT-CEM, HL-60 (TB), MOLT-4, and SR leukemia cell lines and the MCF 7 breast cancer cell line with GI50 values < 0.01 microM. N3-N3 dimer 25i displayed striking potency against leukemia, CNS cancer, melanoma and prostate cancer cell lines with GI50 values < 0.01 microM against all the cell lines and showed the highest overall potency of the agents examined (GMG=0.0120 microM).

Okazaki fragments represent interesting targets for the design of anticancer drugs because of their selective occurrence during DNA replication, a process often elevated in aggressive malignancies. Structural studies have indicated a bend occurs in the helical axis at the junction region (JR) that joins the DNA duplex region (DDR) and the RNA-DNA hybrid duplex region (HDR) of model Okazaki fragments. To identify a structural motif that provides a shape complementary to the Okazaki fragment minor groove, we have investigated the binding of geometrically-constrained bis-distamycins to a model Okazaki fragment, [OKA], with a sequence derived from the genome of simian virus 40 (SV40). Both the JR and the DDR of [OKA] contain consecutive A/T base pairs that could accommodate distamycin binding. Of the six bis-distamycins selected for analysis, the two with a para configuration of the distamycins on the benzene or pyridine scaffold bound [OKA] tightly (Kd approximately 10(-6) M from gel-shift assays; Kd approximately 10(-8) M from deltaT(M)) while the four with a meta orientation did not bind. The two mono-distamycins studied also did not bind [OKA]. Molecular modeling of the complex between the para bis-distamycin MT-9 and [OKA] revealed MT-9 adopted an S- shape complementary to the minor groove of the model Okazaki fragment.

In this review, both cationic and neutral synthetic ligands that bind in the minor groove of DNA are discussed. Certain bis-distamycins and related lexitropsins show activities against human immunodeficiency virus (HIV)-1 and HIV-2 at low nanomolar concentrations. DAPI binds strongly to AT-containing polymers and is located in the minor groove of DNA. DAPI intercalates in DNA sequences that do not contain at least three consecutive AT bp. Berenil can also exhibit intercalative, as well as minor groove binding, properties depending on sequence. Furan-containing analogues of berenil play an important role in their activities against Pneumocystis carinii and Cryptosporidium parvuam infections in vivo. Pt(II)-berenil conjugates show a good activity profile against HL60 and U-937 human leukemic cells. Pt-pentamidine shows higher antiproliferative activity against small cell lung, non-small cell lung, and melanoma cancer cell lines compared with many other tumor cell lines. trans-Butenamidine shows good anti-P. carinii activity in rats. Pentamidine is used against P. carinii pneumonia in individuals infected with HIV who are at high risk from this infection. A comparison of the cytotoxic potencies of adozelesin, bizelesin, carzelesin, cisplatin, and doxorubicin indicates that adozelesin is a potent analog of CC-1065. Naturally occurring pyrrolo[2,1-c][l,4]benzodiazepines such as anthramycin have a 2- to 3-bp sequence specificity, but a synthetic PBD dimer spans 6 bp, actively recognizing a central 5'-GATC sequence. The crosslinking efficiency of PBD dimers is much greater than that of other major groove crosslinkers, such as cisplatin, melphalan, etc. Neothramycin is used clinically for the treatment of superficial carcinoma of the bladder.

A novel amination and 1,2-amino,hydro-elimination reaction occurs between 2,3-diketopyrido[4,3,2-de]quinoline (1, 2) and amino compounds which include α-amino acids and peptides which contain a primary amino group. The amino group undergoes nucleophilic addition to the double bond between C3a and C4 in 2,3-diketopyrido[4,3,2-de]quinoline to form a 3a,4-dihydro-2,3-diketopyrido[4,3,2-de]quinoline. This dihydro intermediate is immediately oxidized by ambient air to produce the more stable aromatic system, 4-(N-alkyl or aryl)-2,3-diketopyrido[4,3,2-de]quinoline (5−12). In the cases of aliphatic amines bearing a β-proton in THF or chloroform, this 4-(N-alkyl)-2,3-diketopyrido[4,3,2-de]quinoline undergoes a 1,2-amino,hydro-elimination reaction to eliminate an alkene and produce the 4-amino-2,3-diketopyrido[4,3,2-de]quinoline (13, 14). In the cases of α-amino acids in aqueous solution, the 4-(N-alkyl)-2,3-diketopyrido[4,3,2-de]quinoline undergoes an amino-transferring reaction, via a mechanism similar to the ac...

Podophyllotoxin is a natural product isolated from Podophyllum peltatum and Podophyllum emodi and has long been known to possess medicinal properties. Etoposide (VP-16), a podophyllotoxin derivative, is currently in clinical use in the treatment of many cancers, particularly small cell lung carcinoma and testicular cancer. This compound arrests cell growth by inhibiting DNA tope­ isomerase II, which causes double strand breaks in DNA. VP-16 does not inhibit tubulin polymerization, however, its parent compound, podophyllotoxin, which has no inhibitory activity against DNA topoisomerase II, is a potent inhibitor of microtubule assembly. 111 addition to these two mechanisms of action, an unknown third mechanism of action has also been proposed for some of the recent modifications of podophyllotoxins. Owing to its severe toxic side effects a number of modifications have been done on podophyllotoxin structure. Some of the congeners exhibited potent antitumor actiivity, of which etoposide and teniposide are in clinical use, NK 611 is in phase II clinical trials and many compounds are in the same line. Recent developments on podophyllotoxins have led structure-activity correlations which have assisted in the design and synthesis of new podophyllotoxin derivatives of potential antitumor activity. Modification of the A-ring gave compounds having significant activity but less than that of etoposide, whereas modification of the B-ring resulted in the loss of activity. One of the modifications in the D-ring produced GP-11 which is almost equipotent with etoposide. E-ring oxygenation did not affect the DNA cleavage which led to the postulation of the third mechanism of action. It has also been observed that free rotation of E-ring is necessary for the antitumor activity. The C4-substituted aglycones have a significant place in these recent developments. Epipodophyllotoxin conjugates with DNA cleaving agents such as distamycin increased the number of sites of cleavage. The substitution of a glycosidic moiety with arylamines produced enhanced activity. Modification in the sugar ring resulted in the development of the agent, NK 611 which is in clinical trial at present. This article review, the progress of podophyllotoxins from its early applications in folk medicine to the most recent modifications and the mechanism(s) of action, pharmacology and the structure-activity relationships.

Photodynamic therapy (PDT) has been considered as a potential therapy for superficial bladder carcinomas. Cutaneous photosensitivity and reduction of bladder capacity are the two well-known complications following systemic administration of the commonly used photosensitizer, Photofrin II® (PII). The objective of the present study was to evaluate whether intravesical. (i.b.) instillation of photosensitizers for PDT of bladder cancer might be a more suitable treatment method. Female Fischer rats were utilized to develop orthotopic and heterotopic bladder tumor models. Rats bearing orthotopic bladder tumors were treated either intravesically or intravenously with graded doses of 5-aminolevulinic acid (ALA) or PII. Normal rats received the same doses of ALA or PII. As well, rats bearing heterotopic tumor were studied for comparison. The biodistribution times (times allowed for tissue uptake and bioconversion following drug administration) were 2, 4 or 6 h. Porphyrin fluorescence intensities within tumor, urothelium, submucosa, bladder muscularis and abdominal muscle were quantitated by confocal laser scanning microscopy. Following intravenous (i.v.) injection of ALA, tumor protoporphyrin IX (PpIX) levels peaked at 4 h and diminished by 6 h. The PpIX ratios of tumor-to-bladder mucosa, submucosa and muscle layers were 3:1, 5:1 and 8:1, respectively, 4 h following 1000 mg/kg ALA injection. After ALA instillation, the optimal biodistribution time appeared to be 4 h. Bladder instillation provided comparable tumor labeling with the i.v. route, but lost selectivity of PpIX accumulation between tumor and normal urothelium. The PpIX ratio of tumor-to-bladder muscularis was 5:1. After i.b. instillation of PII, porphyrin fluorescence was detected only within tumor and urothelium, while porphyrin fluorescence was mainly located in bladder submucosa following i.v. injection. Intravesical administration of ALA or PII might be feasible for PDT of superficial bladder cancers.

A concise five step synthesis of the pyrroloquinoline related to makaluvamine, and discorhabdine from 1,2-dimethoxy-3,5-dinitrobenzene is developed.

Hypocrellins are perylenequinone pigments with substantial absorption in the red spectral region and high singlet oxygen yield. They are available in pure monomeric form and may be derivatized to optimize properties of red light absorption, tissue biodistribution and toxicity. In vitro screening of synthetic derivatives of the naturally occurring compound, hypocrellin B (HB), for optimal properties of cyto-(dark) toxicity and phototoxicity resulted in selection of three compounds for preclinical evaluation: HBEA-R1 (ethanolaminated HB), HBBA-R2 (butylaminated HB) and HBDP-R1 [2-(N,N-dimethylamino)-propylamine-HB]. Extinction coefficients at 630 nm (epsilon 630) are 6230, 6190 and 4800, respectively; and 1O2 quantum yields, phi, 0.60, 0.32 and 0.42. Intracellular uptake is essentially complete within 2 h (HBEA-R1, HBBA-R2) and 20 h (HBDP-R1). Greatest uptake is associated with lysosomes and Golgi. The HBEA-R1 and HBBA-R2 elicit phototoxicity in vitro primarily via the type II mechanism, with some type I activity under stringently hypoxic conditions. Transcutaneous phototherapy with HBEA-R1 permanently ablates EMT6/Ed tumors growing in the flanks of Balb/c mice, with minimal cutaneous effects. The HBBA-R2 does not elicit mutagenic activity in strains TA98 and TA100 of Salmonella typhimurium. Further development of selected hypocrellin derivatives as photosensitizers for photodynamic therapy is warranted.

A series of hybrid molecules containing the pyrroloquinoline nucleus covalently linked to polypyrroleamide DNA minor groove binder were synthesized and evaluated for in vitro cytotoxic activity.

The bleomycins are a group of glycopeptide anticancer cytotoxic agents which have been used in the clinical treatment of several human malignancies as single or combination chemotherapy for over two decades. However, the risk of dose-dependent pulmonary toxicity, which ultimately results in pulmonary fibrosis, limits the scale of application. Meanwhile, the unique mechanism of the antitumour effects of bleomycins has also attracted considerable interest from biologists. Extensive studies at the molecular level have provided a guide to attempts to obviate the pulmonary toxicity. Recent progress made in the areas of drug delivery, electropermeabilisation and conjugate synthesis has provided valuable additional information to improve bleomycin chemotherapy. The patents and publications discussed in this review are selected from those covering the period from 1992 to date based on a Chemical Abstracts search.

Oligopeptides distamycin and its analogues can bind cooperatively to the minor groove of certain DNA sequences in a closely compacted antiparallel side by side motif, where the positively charged ends are located in the carboxyl termini of such peptidic structures. In order to dissect its physical underpinning, the role of charge in maintaining the integrity of this novel motif is explored by using three judiciously designed distamycin analogues possessing either no charge or with charge ends located in the amino termini. Preliminary experiments by CD and ethidium fluorescence displacement suggested that the charge plays an role in influencing the degree of binding cooperativity as well as binding strength, although qualitatively the dimeric binding remains cooperative.

A series of new camptothecin derivatives bearing five-membered ring heterocycle containing substituents in the 10-position were synthesized and evaluated for in vitro cytotoxic activity. Camptothecin derivatives bearing a pyrrole or a thiophene ring were significantly more potent than camptothecin, however those bearing furan were less potent than camptothecin.

Novel oligopeptide and amino alkyl substitued indolocarbazoles were synthesized and characterized with respect to inhibition of protein kinases C and A. In both series potent and selective PKC inhibitors could be identified. Structure activity relationships are discussed.

Our research group is currently exploring the use of hypocrellins as potential photosensitizers for photodynamic therapy (PDT). The purpose of this study is to investigate the synthesis and biodistribution of 14 C-labelled Hypocrellin B. Radiolabelled hypocrellin-B (HB) with the 14 C atom incorporated in either or both the 4- and 13-methoxy groups was synthesized with a specific activity of 2.11 mCi per mmol. The purified, 14 C-HB, prototype photodynamic therapy photosensitizer was used to determine the kinetics of uptake in EMT6/Ed cells in monolayer culture, and the kinetics of tumor and tissue distribution in Balb/c mice bearing the EMT6/Ed tumor.

A general synthetic route to cross-linked homodimeric bis-lexitropsins connected through the nitrogens of the central pyrrole ring with polymethylene chains (19a-c, 20a and 21a) is described. These compounds were designed for efficient DNA minor groove binding

The synthesis of specifically 15 N labelled trans- and cis-isomers of bis-netropsins derived from 2-butene-1,4-dicarboxylate as the central linker, namely the (E)- and (Z)-forms of N-(2-[2-[(3-amino-3-iminopropyl)( 15 N)aminocarbonyl]-1-methylpyrrole-4-aminocarbonyl]-1-methylpyrrol-4-yl], N'-[2-[2-[(3-amino-3-iminopropyl)aminocarbonyl]-1-methylpyrrole-4-aminocarbonyl]-1-methylpyrrol-4-yl]-2-butenediamide (18 & 28) are described. A highly convergent synthetic route was adopted for the preparation of the trans-derivative starting from N-methyl-4-nitro-2-trichloroacetylpyrrole and fumaroyl chloride. The most efficient methods of coupling aminopyrrole intermediates with activated carboxylic acid derivatives were utilized and the 15 N-labelled moieties were incorporated in the later stages of the synthesis. The preparation of the cis-derivative, starting with maleic anhydride, required a modification of the above strategy due to the nature of products formed upon initial coupling with aminopyrrole derivatives. 1 H- and 15 N-NMR were used to fully characterize the final products. The 1 H NMR experiment allowed the assignment of an intramolecular hydrogen bond for the cis bis-netropsin 28

To assess the role of the amine and ester containing oligopeptide side-chains in bis-indole protein kinase C inhibitors, six novel hybrids in this series were synthesized. These new compounds displayed effective inhibitory activity against protein kinase C-α.

The concept of lexitropsins, or information-reading molecules, is introduced within the antigene strategy as an alternative to, and complementary with, the antisense approach for cellular intervention and gene control. Consideration is given to alternative approaches to the development of DNA sequence selective binding agents because of their potential applications in diagnosis and treatment of cancer as well as in molecular biology. The chemical, physical, and pharmacological factors involved in the design of effective lexitropsins are discussed and illustrated with experimental results. Among the factors contributing to the molecular recognition processes are: the presence and disposition of hydrogen bond accepting and donating groups, ligand shape, chirality, stereochemistry, flexibility, and charge. For longer ligands, such as are required to target unique sequences in biological systems (14–16 base pairs), the critical feature is the phasing or spatial correspondence between repeat units in the ligand and the receptor. The recently discovered 2:1 lexitropsin-DNA binding motif provides a further refinement in molecular recognition in permitting discrimination between GC and CG base pairs. The application of these factors in the design and synthesis of novel agents which exhibit anticancer, antiviral, and antiretroviral properties, and in the inhibition of critical cellular enzymes including topoisomerases, is discussed. The emerging evidence of a relationship between sequence selectivity of the new agents and the biological response they invoke is also described. © 1995 Wiley-Liss, Inc.

The thermally induced [2 + 3] cycloadditions of certain monocyclic aziridines to dimethyl 1-cyclobutene-1,2-dicarboxylate are described. The structures of the resulting bicyclic adducts were established unambiguously by X-ray analyses. The stereochemistries of the [2 + 3] adducts were interpreted in terms of dipole–dipole interactions and secondary orbital interactions. In certain cases an initial thermal conrotatory ring opening of the cyclobutene to 2,3-di(methoxycarbonyl)-1,3-butadiene precedes the [2 + 3] cycloaddition, affording the unexpected pyrrolidine adducts 12a and 12b. The structures and stereochemistries of the latter established by X-ray analysis strongly suggest that secondary orbital interactions between the phenyl and ester groups control and stereochemistry of the reactions.

The synthesis of covalently cross-linked bis-lexitropsins 14 , 15 and 16 designed to bind to specific nucleotide sequences in the minor groove of double-helical DNA is described.

A highly efficient method is described for the synthesis of staurosporine aglycone 3 from the readily available dibromomaleic acid in six steps.

The binding mode of a series of bis-benzimidazole analogues of Hoechst 33258 to a variety of DNAs and polynucleotides has been investigated by electric linear dichroism. Two groups of compounds were examined: (i) benzoxazole and pyridoimidazole derivatives and (ii) pyridoimidazole analogs substituted with an N-alkoxyalkyl group either directed towards the minor groove or directed away from the minor groove. The ELD data indicate that the mode of binding of these drugs varies significantly with the sequence of the target DNA sequence. The DNA binding properties of these drugs are related to their topoisomerase inhibitory properties.

The design and synthesis of 1a – e , functional models for bleomycin are described in which AMPHIS, a metal-complexing model of bleomycin, and a distamycin moiety are connected with a series of linkers. Studies on the rates of DNA breakage and a mobility assay of DNA cleavage ability show that trans-1,2-disubstituted cyclopropane units are the best linkers amongst those examined.

Consideration is given to alternative approaches to the development of DNA sequence selective binding agents because of their potential applications in diagnosis and treatment of cancer as well as in molecular biology. The concept of lexitropsins, or information-reading molecules, is introduced within the antigene strategy as an alternative to, and complementary with, the antisense approach for cellular intervention and gene control. The chemical, physical and pharmacological factors involved in the design of effective lexitropsins are discussed and illustrated with experimental results. Among the factors contributing to the molecular recognition processes are: the presence and disposition of hydrogen bond accepting and donating groups, ligand shape, chirality, stereochemistry, flexibility and charge. For longer ligands, such as are required to target unique sequences in biological systems (14-16 base pairs), the critical feature is the phasing or spatial correspondence between repeat units in the ligand and the receptor. The recently discovered 2:1 lexitropsin-DNA binding motif provides a further refinement in molecular recognition in permitting discrimination between GC and CG base pairs. The application of these factors in the design and synthesis of novel agents which exhibit anticancer, antiviral and antiretroviral properties, and inhibition of critical cellular enzymes including topoisomerases is discussed. The emerging evidence of a relationship between sequence selectivity of the new agents and the biological responses they invoked is also described.

The synthesis, diastereomeric separation, and characterization are described for a series of novel O-(2,2,2-trifluoroethyl)-3′,5′-dinucleoside phosphates, required for incorporation into antisense probes in the magnetic resonance imaging investigation of biodistribution. Preliminary assignment of the absolute configuration of the Rp and Sp diastereomers is made on the basis of 31 P NMR spectra.

When calphostin C was illuminated with visible light, the semiquinone radical, singlet oxygen, and superoxide anion radical were detected. The formation of the semiquinone radical and activated oxygen species and the transformations and competitions between them depend upon the quinone and oxygen concentrations, time and intensity of illumination, and the nature of the substrate. In anaerobic solution, the semiquinone radical was predominantly photoproduced via the self-electron transfer between the excited and ground species. In aerobic solution, singlet oxygen is the principal product in the photosensitization of calphostin C. In addition to singlet oxygen, superoxide anion radical is also generated by the quinones upon illumination in aerobic solution, but to a lesser extent than singlet oxygen. The superoxide anion is produced via the reduction of oxygen by the semiquinone radical, and this process is significantly enhanced by the presence of electron donors.

A series of hybrids incorporating propargylic sulfones and minor groove bindin goligopeptide carriers 2-11 were synthesized and their abilities to cleave DNAd have been demonstrated.

The syntheses of 1a-c, functional models for bleomycin, which are composed of a simplified metal-complexing moiety of bleomycin and poly-N-methylpyrrole peptides are described. Their functional cleavage of DNA in the presence of reductants is demonstrated.

Visible light illumination of solutions of perylenequinonoid pigments generates the corresponding semiquinone radicals, singlet oxygen, superoxide anion radical, hydroxyl radical and hydrogen peroxide. In anaerobic solution, the semiquinone radicals are predominantly photoproduced via the self-electron transfer between the excited and ground state species. In aerobic solution, singlet oxygen is the principal product in the photosensitization of perylenequinonoid pigments. The 3,10-dihydroxy-4,9-perylenequinonoid chromophore was shown to be the necessary structural requirement for the generation of singlet oxygen, and the side-chains of the quinones had little effect on the production of singlet oxygen. This conclusion is useful in the development of more efficient photodynamic therapeutic agents than natural perylenequinonoid pigments themselves. Such agents should ideally contain the 3,10-dihydroxy-4,9-perylenequinonoid chromophore to produce singlet oxygen together with appropriate elaborated side-chains to permit the selective localization of the sensitizer in tumor tissue. In addition to singlet oxygen, superoxide anion radical is generated by the perylenequinones on illumination in aerobic solution, but to a lesser extent than singlet oxygen, via the reduction of oxygen by the corresponding semiquinone radicals. This latter process is significantly enhanced by the presence of electron donors.

Carbazomycin B (1) was synthesized by radical cyclization of the sulfonamide 14 (Scheme III), followed by deprotection and dehydrogenation

Three novel hypocrellin B (HB) derivatives required for their potential in photodynamic therapy have been synthesized. The possible reaction mechanisms and the properties of resulting HB derivatives are discussed.