Synthesis and antitumor activity of duocarmycin derivatives: modification at C-8 position of A-ring pyrrole compounds bearing the simplified DNA-binding groups

A series of the 8-O-substituted A-ring pyrrole derivatives of duocarmycin bearing the simplified DNA-binding moieties such as cinnamoyl or heteroarylacryloyl groups were synthesized, and evaluated for in vitro anticellular activity against HeLa S3 cells and in vivo antitumor activity against murine sarcoma 180 in mice. In addition, the stability of the 8-O-substituted analogues in aqueous solution and the conversion to their active form (cyclopropane compound) from the 8-O-substituted analogues in mice or human serum were examined. The 8-O-substituted A-ring pyrrole derivatives bearing the simplified DNA-binding moieties showed remarkably potent in vivo antitumor activity and low peripheral blood toxicity compared with the 8-O-substituted A-ring pyrrole derivatives having the trimethoxyindole skeleton in segment-B (Seg-B), which were equal to 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 4'-methoxycinnamates and 4'-methoxy-beta-heteroarylacrylates. Moreover, among 8-O-substituted analogues, several compounds can be chemically or enzymatically converted to their active form in human serum. This result indicated that new 8-O-substituted derivatives were different prodrugs from KW-2189 and 8-O-substituted analogues being the same type of prodrug as KW-2189.     

Synthesis and antitumor activity of duocarmycin derivatives: A-ring pyrrole compounds bearing beta-(5',6',7'-trimethoxy-2'-indolyl)acryloyl group

A series of A-ring pyrrole derivatives of duocarmycin bearing beta-(5',6',7'-trimethoxy-2'-indolyl)acryloyl group were synthesized, and evaluated for in vitro anticellular activity against HeLa S3 cells and in vivo antitumor activity against murine sarcoma 180 in mice. New Seg-B analogues bearing beta-(5',6',7'-trimethoxy-2'-indolyl)acryloyl group containing double bond as spacer had lower peripheral blood toxicity than the derivatives bearing 5',6',7'-trimethoxyindole-2'-carboxyl group in Seg-B of the natural type. Moreover, most of them exhibited potent antitumor activity against in vivo murine tumor models.     

Synthesis and antitumor activity of novel C-8 ester derivatives of leinamycin

A novel series of C-8 ester derivatives of leinamycin are described. Condensation of N-substituted amino acids or carboxylic acids containing polyether moiety with leinamycin resulted in the C-8 ester derivatives with good antitumor activity in several experimental models. Among these derivatives, compound 4e, which has five ethylene glycol ether units in the C-8 acyl group, showed potent antitumor activity against human tumor xenograft. Combination with the modification of the dithiolanone moiety was applied to these C-8 ester derivatives and some of them also showed good antitumor activity.     

Synthesis and antitumor activity of water-soluble duocarmycin B1 prodrugs

The water-soluble duocarmycin B1 prodrugs such as glycoside 3, phosphate 4 and carbamate 5 were synthesized for improving biological and pharmaceutical profiles of duocarmycin. Among these prodrugs, N-methylpiperazinylcarbamoyl derivative 5 exhibited potent antitumor activity against several human tumors in vivo.     

Synthesis and cytotoxic activity of A-ring modified betulinic acid derivatives

New A-ring modified betulinic acid derivatives having small steric hindrance were prepared and tested for cytotoxic activity on 3 cancer cell lines: 10 compounds showed stronger cytotoxic activity than betulinic acid. Especially, the compounds bearing 1-ene-3-oxo with electron-withdrawing groups at C2 showed strong cytotoxicity.     

Synthesis and antitumor activity of 7-ethyl-9-alkyl derivatives of camptothecin

A series of new camptothecin derivatives, as topoisomerase I inhibitor, were synthesized to identify potent antitumor agents. The synthesis method was based on the Claisen rearrangement of 10-allyloxy-7-ethylcamptothecin. All of the compounds were assayed for cytotoxicity against two human tumor cell lines, Bel7402, HCT116, and showed good potency in vitro. Compounds 2, 4, 9, were assessed for the stability of lactone in human plasma. And then compound 2 was tested for antitumor activity in vitro against mouse tumor sarcoma-180. The results suggested that the small alkyl groups in the both 7- and 9-positions of camptothecin could promote liposolubility, antitumor activity in vitro and vivo, though did not bring much increase of the stability of lactone.     

Synthesis and antiproliferative activity of A-ring aromatised and conduritol-like steroidal compounds

A simple approach to aromatization of steroidal quinols and epoxyquinols using a catalytic amount of TMSOTf is reported. Beside acetylation of the angular OH, the acid-catalyzed (TfOH) dienone-phenol rearrangement occurred affording "para" products, or in the case of blocked position 4, the acetoxy group 1,2-migration leads to the formation of "meta" products. Using epoxyquinol derivative as a substrate, the acetoxy group elimination was observed, followed by acid-catalyzed epoxy-ring opening and subsequent double bond migration, giving as a final product Delta(9,11)A-ring aromatized compounds. Synthesis of conduritol-like compounds and structure confirmation by X-ray crystallography of the precursor of steroidal conduritol is also described. In addition, the results of extensive antiproliferative screening against a panel of 60 cancer cell lines are presented.     

Synthesis and antitumor activity of s-tetrazine derivatives

Fifty-five compounds of s-tetrazine derivative including hexahydro-, 1,6-dihydro, 1,4-dihydro-, 1,2-dihydro- and aromatic s-tetrazine were prepared. Their antitumor activities were evaluated in vitro by MTT method for P-388 cell and SRB method for A-549 cell. The results show that there are 9 compounds which in 10(-6) microM have more than 50% inhibition rate to A-549 cancer cell growth, and 7 compounds in 10(-6) microM have more than 50% inhibition rate to P-388 cancer cell growth. The IC(50) of compound 3q for P-388, Bel-7402, MCF-7 and A-549 are 0.6 microM, 0.6 microM, 0.5 microM and 0.7 microM, respectively. So s-tetrazine derivative is a kind of compound which possesses potential antitumor activities and is worth to research further.     

Synthesis and biological activities of hapalosin derivatives with modification at the C12 position

Among the hapalosin derivatives synthesized, the compounds carrying methyl (5a), methylthioethyl (5d) and phenylmethyl (5e) groups at the C12 position possess only the cis-peptide structure, in contrast to the cases of 5b and 5c. In addition to their conformational stability, the biological activities of the compounds were determined in relation of the P-glycoprotein-mediated MDR-reversing activity and induction of apoptosis.     

Novel derivatives of deoxycholic acid bearing aliphatic or cyclic diamine moieties at the C-3 position: Synthesis and evaluation of anti-proliferative activity

A new library of deoxycholic acid derivatives bearing nitrogen-containing moieties at the C-3 position was synthesised from epoxy derivative 1 via an epoxide ring-opening reaction promoted by aliphatic or cyclic diamines and fully characterised by NMR and mass-spectroscopy. The synthesised compounds were screened for cytotoxicity against four human tumour cell lines. The results showed that some of the novel diamine-bearing derivatives displayed improved anti-proliferative activities over the parent compound DCA. Among them, a 1-methylpiperazine containing compound (6) showed promising activity and the highest selectivity against tumour cells of enterohepatic origin (HepG2: IC₅₀ = 3.6 µM, SI = 9.0; HuTu-80: IC₅₀ = 4.6 µM, SI = 6.9) and was identified as a lead molecule.     

Synthesis and antitumor activity of cholest-4 alpha-methyl-7-en-3beta-ol derivatives

Cholest-4 alpha-methyl-7-en-3beta-ol (1) has potent inhibitory activity against pc 12 tumor with 0.5043 ratio (10 microg/mL). This paper describes a series of structural modification of this compound, which focus on 3beta-hydroxyl group and 7(8)-double bond. The synthesized derivatives of 1 were tested for human cancer cell lines including colon cancer (HCT-8), liver cancer (BEL-7402) and nasopharyngeal cancer (KB) cells. The results showed that cholest-4 alpha-methyl-8-en-3beta,7 alpha-diol 6a inhibits KB cell significantly with IC(50) 1.32 x 10(-9)microg/mL. In addition, the cytotoxic properties of this compound against HCT-8 and BEL-7402 are excellent with IC(50) 1.2 microg/mL.     

Synthesis and antitumor activity of the hexacyclic camptothecin derivatives

A series of hexacyclic camptothecin derivatives were synthesized to test for antitumor activity as topoisomerase I inhibitor. The strategy of synthesis was used for the formation of additional furan and dihydrofuran rings fused with 9- and 10-positions of camptothecin. All of the hexacyclic camptothecins were assayed for cytotoxicity against four human tumor cell lines, HL60, BEL-7402, HCT-116, and HeLa, and showed very impressive cytotoxicity activity in vitro. Enzyme activity of the hexacyclic camptothecins was evaluated, being equal or superior to that of SN-38. The stability of four compounds was assessed in human plasma. Two of these compounds were chosen to test for antitumor activity in vivo against Sarcoma-180. The results suggested that additional furan and dihydrofuran rings could improve the antitumor activity in vitro and vivo, though the stability of the lactone ring did not increase.     

Synthesis and antitumor activity of 10-arylcamptothecin derivatives

A series of 10-arylcamptothecin derivatives was designed and synthesized. The key step of the synthesis was achieved by employing Suzuki cross-coupling chemistry. All of the new derivatives were tested for cytotoxicity against three human tumor cell lines, BEL-7402, A549, and HL-60; most of the derivatives exhibited potent cytotoxicity. The stability study showed that compound 30 was more stable than its lead compound 10-hydroxycamptothecin under the physiological condition. Mechanistic study demonstrated that compound 30 and its hydrochloride 31 had a pharmacological profile similar with camptothecin.     

Synthesis and antitumor activity of 4-hydroxycoumarin derivatives

A series of 4-hydroxycoumarin derivatives was prepared and evaluated for antitumor activity. The key fragments were 2a-c, 5c, 12b, 13b, 17, and 18 which were prepared via dianion ring cyclization, Friedel-Crafts acylation, and Reformatsky reaction. Compound 20b showed the most potent antitumor activity among the total 12 derivatives and compounds 19a and 19b exhibited efficacy comparable to etoposide in vitro antitumor activity.     

Biological evaluation of new antitumor taxoids: Alteration of substitution at the C-7 and C-10 of docetaxel

A series of new docetaxol analogues have been designed and synthesized. And their cytotoxicities against cancer cells have been evaluated by MTT method. Most of these compounds showed selective inhibitions on human cancer cell lines. Among them, compound 8 exhibited higher inhibitory activity than Paclitaxel (Taxol) against several cancer cell lines. This work indicated that appropriate modification at C-7 and C-10 of docetaxel might be a promising approach for this unique class of anticancer compounds.     

Synthesis and topoisomerase poisoning activity of A-ring and E-ring substituted luotonin A derivatives

A series of A-ring and E-ring analogues of the natural product luotonin A, a known topoisomerase I poison, was evaluated for growth inhibition in human carcinoma and leukemia cell lines. Rational design of structures was based on analogues of the related alkaloid camptothecin, which has been demonstrated to exert cytotoxic effects by the same mechanism of action. When compared to luotonin A, several compounds exhibited an improved topoisomerase I-dependent growth inhibition of a human leukemia cell line.     

Synthesis and antitumor activity of feruloyl and caffeoyl derivatives

We developed two efficient protocols for the synthesis of feruloyl and caffeoyl derivatives from commercial vanillin and veratraldehyde. Pharmacological activities were assessed against a panel of human cancer cell lines in vitro. Most synthesized compounds demonstrated attractive cytotoxicity. Several new compounds demonstrated significant antiproliferative and cytotoxic activities against HeLa and Bewo tumor cell lines. In particular, 5-nitro caffeic adamantyl ester showed broad spectrum of tumor inhibition in 10 cell lines, and reduced tumor weight by 36.7% in vivo when administered at a dose of 40 mg kg⁻¹.     

Synthesis of lipid derivatives of pyrrole polyamide and their biological activity

Novel fatty acyl and phospholipid derivatives of pyrrole polyamide were synthesized. Their cytotoxicity against a cancer cell line of MT-4 cells and those infected by human immunodeficiency virus (HIV) was examined. Although no anti-HIV activity was found, their cytotoxicitty against the cancer cells was significantly enhanced by introducing a lipophilic group into the pyrrole polyamide.     

Synthesis and antitumour activity of derivatives of curdlan and lichenan branched at C-6.

Derivatives of curdlan and lichenan, linear (1----3)-beta-D- and (1----3/1----4)-beta-D-glucans, respectively, have been synthesised having alpha-L-arabinofuranosyl, alpha-L-rhamnosyl, beta-D-glucosyl, and beta-gentiobiosyl side chains attached at positions 6. These water-soluble derivatives, obtained by condensation of the 2,4- and 2,4-/2,3-di-O-phenylcarbamoyl derivatives of curdlan and lichenan, respectively, with appropriate ortho esters followed by saponification, were characterised by methylation analysis, g.p.c., and interaction with Congo Red. The curdlan derivatives and the lichenan derivative with few glucosyl branches were active against the Sarcoma 180.     

Synthesis and Biological Activity of Some Juvenile Hormone Analogs Lacking the Alkyl Substituents at C-7 or Both at C-3 and at C-7

Two groups of juvenile hormone analogs were synthesized. One lacks the alkyl substituent at C?7. The other possesses the alkyl substituents neither at C?3 nor at C?7. These analogs were almost inactive on Bombyx mori L. Some of them with the alkyl substituent at C?3, however, were active on Tenebrio molitor L. This indicates the very narrow sensitivity of Bombyx mori L. to juvenile hormone analogs.