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A series of derivatives of meso-tetraphenylporphine, with neutral, acidic and basic functional groups, has been prepared. Several of these compounds were synthesized directly via the Rothemund reaction, under a variety of conditions to obtain optimal yields; others were prepared by interconversions of various functional groups. Drastic reaction conditions employed for hydrolysis, alcoholysis, o r lithium aluminum hydride reduction did not affect the porphine ring system. The two amino derivatives showed anomalous spectra in the visible range.Synthetic porphyrins are of potential interest in medicinal chemistry for a variety of reasons: (1) they a r e structurally related to important biological substances (heme, vitamin Biz); ( 2 ) they a r e powerful metal chelating agents; (3) they absorb radiation energy a t certain wavelengths, including the visible spectral range, and may act either a s radiation sensitizers o r protecting agents against radiation; (4) they show selective tissue distribution properties. Hematoporphyrin reportedly accumulates in tumors and other rapidly growing tissues (3-5) and was used a s a fluorescent indicator for the delineation of neoplastic tissue in cancer patients (6). A sulfonated derivative of meso-tetraphenylporphine was recently reported to be even more selective and to attain a 50-100 times greater tumor concentration than hematoporphyrin (7-9). It would seem, therefore, that such compounds may be used a s tumor-selective radiation sensitizers, and in the form of their chelates either with a toxic metal ( e . g . , Hg) (10) o r , with a gamma-ray emitting radioistope ( e . g . , Co5?) (9), a s potential chemotherapeutic agents.In order to establish the effects of various functional groups in the porphyrin molecule on the solubility, tissue distribution and specificity of binding to certain cell-constituents, a series of new meso-tetraphenylporphine derivatives, substituted in the para positions with acidic, basic or neutral groups (11-VIII), were synthesized and studied. The previously known meso-tetra-p-tolylporphine (I) was prepared in serial experiments designed to study the optimal methods and conditions for the synthesis of these compounds.Compounds I to V were prepared directly by various applications of the Rothemund reaction, i. e . , by condensation of the appropriately substituted benzaldehyde with pyrrole. Compounds VI to VIII were prepared by chemical conversion from I1 and 111 .Two major variations of the Rothemund reaction a s applied to the synthesis of mesotetraphenylporphine and some of i t s derivatives were found in the literature:(A) Heating a mixture of pyrrole with the appropriate aldehyde in a sealed bomb at high pressure and temperature, usually with pyridine as a solvent. This method originally used by Rothemund (11,12) gave extremely low yields (~1%). When the reaction was conducted in the presence of metal salts (Calvin, I, R CH3 3 --' 111, R = CN VII. R = COOH Vlll. R CH20H

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Intracellular polyamine pools are partially maintained by an active transport apparatus that is specific for and regulated by polyamines. Although mammalian transport activity has been characterized by kinetic studies, the actual protein itself has yet to be identified, purified, or cloned. As one approach to this problem, we attempted photoaffinity labeling of plasma membrane proteins using two specifically designed and synthesized polyamine conjugates as photoprobes. The first is a spermidine conjugate bearing the photoreactive moiety 4-azidosalicylic acid at the N 4 position via an alkyl linkage, and the second is a norspermine conjugate with 4-azidosalicylic acid at the N 1 position via an acyl linkage. Labeling of murine L1210 lymphocytic leukemia cells was carried out at 4°C to promote selective alkylation of cell surface proteins. Separation of plasma membrane proteins from cells cross-linked with the N 4 -spermidine conjugate by SDS-polyacrylamide gel electrophoresis revealed two heavily labeled proteins at ϳ118 and ϳ50 kDa (designated p118 and p50, respectively). Band p118 was more well defined and much more intensely labeled. Analogous proteins were also observed in human U937 lymphoma cells. Specificity of labeling was strongly suggested by competition with polyamines and analogs during labeling and further indicated by the nearly identical labeling of the same protein by the N 1 -norspermine photoprobe but not by the unconjugated photoreagent. Neuraminidase pretreatment of L1210 cells increased mobility of the p118, suggesting that it was glycosylated and, thus, of plasma membrane origin. In transport-deficient L1210 cells, p118 and p50 were found to have a slightly higher molecular mass and were accompanied by a less distinct protein band (ϳ100 kDa). These findings indicate the presence of a polyamine binding protein at the surface of murine and human leukemia cells, which could be directly or indirectly related to the polyamine transport apparatus.

5-Mercaptouracil (I) and its Ni deoxyribosides (III) undergo rapid autoxidation in aqueous solutions to the corresponding disulfides. This reaction was found to be dependent on the presence of trace amount of Fe3 + in the buffer solution. Addition of EDTA inhibited the oxidation and changed its over-all kinetic order. Addition of Fe salts at low substrate concentrations resulted in an initial rate increase, up to a certain "saturation" concentration of iron which was dependent upon, but much smaller than, the substrate concentration. The pH dependence of the oxidation rate closely paralleled that of the ionization of the SH group; ionization of the second proton of I (Ni-H) further increased, while that of III (N3-H) decreased the rate. The kinetic data are consistent with the assumption that the autoxidation reactions depend on the formation of a 1:3 chelate between the Fe3+ and the thiolate ions and on its subsequent homolytic breakdown, to a Fe11 complex and a thiyl radical, the latter process being significantly promoted by the ionization of the Ni-H proton. Based on the proposed mechanistic scheme, it was possible to derive for the autoxidation reactions a general rate equation which satisfies all kinetic results.An antimetabolite of thymine,3 5-mercaptouracil tx (I), undergoes extremely rapid autoxidation in aqueous solutions to the corresponding disulfide II. This reaction is so fast even in stoppered cuvettes that the correct ultraviolet spectra and p constants of I could be determined only in the presence of a reducing agent, dithiothreitol.4 The recently synthesized anomeric 5-mercaptodeoxyuridines5 (III, a and ß) are oxidized under the same conditions at appreciably slower rate.

The syntheses of three bis( l-aziridinyI)phosphmyl carbamates (including the new experimental cancer drugs, I and III), as well as of some structurally related new carbamates and carbamides, are reported. These compounds were prepared through the intermediate dichloroisocyanatophosphine oxide, or through pyrolysis of I.Three years ago, in a joint communication3 with our biological collaborators, we reported on a new series of compounds termed "dual antagonists," which exhibited significant inhibitory activities against a broad spectrum of experimental animal tumors. Since then, two of these compounds, "AB-100" (I)4 and "AB-103" (III),6 have been undergoing extensive clinical trial against various forms of neoplastic disease in humans, and they were the subject of recent publications by several groups of investigators.6-10 The present paper describes the syntheses of these compounds and of some of their chemical analogs."Dual antagonists" are designed to incorporate the biologically essential structural features of two different but synergistic inhibitors into a single molecule.11 Among the compounds reported in the '/. B. Papaxastassiott and T.

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